Anthelmintic compounds comprising a thienopyridine structure

ABSTRACT

The present invention relates to new anthelmintic compounds. These compounds can for example be used in the treatment of the kind of worm disease caused by helminths such as  Dirofilaria , in particular  Dirofilaria immitis.

The present invention relates to new anthelmintic compounds. Thesecompounds can for example be used in the treatment of the kind of wormdisease caused by helminths such as Dirofilaria, in particularDirofilaria immitis.

BACKGROUND

Several severe animal diseases are caused by helminths, wherein thehelminths can be categorized in the following groups of a) cestodes:e.g. Anaplocephala spp.; Dipylidium spp.; Diphyllobothrium spp.;Echinococcus spp.; Moniezia spp.; Taenia spp.; b) trematodes e.g.Dicrocoelium spp.; Fasciola spp.; Paramphistomum spp.; Schistosoma spp.;or c) nematodes, e.g. Acanthocheilonema spp.; Ancylostoma spp.; Anecatorspp.; Ascaridia spp.; Ascaris spp.; Brugia spp.; Bunostomum spp.;Capillaria spp.; Chabertia spp.; Cooperia spp.; Cyathostomum spp.;Cylicocyclus spp.; Cylicodontophorus spp.; Cylicostephanus spp.;Craterostomum spp.; Dictyocaulus spp.; Dipetalonema spp; Dirofilariaspp.; Dracunculus spp.; Enterobius spp.; Filaroides spp.; Habronemaspp.; Haemonchus spp.; Heterakis spp.; Hyostrongylus spp.;Metastrongylus spp.; Meullerius spp. Necator spp.; Nematodirus spp.;Nippostrongylus spp.; Oesophagostomum spp.; Onchocerca spp.;Onchocercidae spp; Ostertagia spp.; Oxyuris spp.; Parascaris spp.;Stephanurus spp.; Strongylus spp.; Syngamus spp.; Toxocara spp.;Strongyloides spp.; Teladorsagia spp.; Toxascaris spp.; Trichinellaspp.; Trichuris spp.; Trichostrongylus spp.; Triodontophorous spp.;Uncinaria spp., and/or Wuchereria spp.

The above helminths cause helminthiasis also known as worm infection.These helminths often live in the gastrointestinal tract of their host,but they may also burrow into other organs, where they inducephysiological damage. For example, Ascaridia spp. are reported to causefrom infections of the small intestine to partial or even totalobstruction of the gastrointestinal tract of the affected animal, inparticular feather animals such as birds. Further, another helminth,Haemonchus spp. are known to affect animals like sheep and goats,wherein such infestation often results in the attachment in the abomasalmucosa for sucking blood from the host. Thus, the affected animal canget anaemic and short of breath. Even further, Oesophagostomum spp. areknown to cause a nodule formation in the intestines of its infectedhosts, which may result in dysentery.

Furthermore, heartworm disease, also known as cardiovasculardirofilariasis, is a serious and mostly fatal disease that may affectinner organs such as lung and heart in pets and certain mammals. Thedisease is caused by parasitic nematodes, Dirofilaria immitis, which inthe adult state can have a length up to about 30 centimetres and athickness of about 1 millimetre. These nematodes live in the heart, thelung and associated blood vessels causing severe lung disease, heartfailure and damage to other inner organs such as the liver and kidneys.Thus, heartworm infection may result in complication for the host,typically culminating in the host's death.

The heartworm disease is known to affect pets, in particular dogs, whichare considered as the definitive host. However, also cats, ferrets,wolves, coyotes, jackals, foxes, bears, sea lions and in very rare caseseven humans (zoonosis) may be affected by heartworms.

Heartworms have to go through different stages before they become adultsresiding in the host animal. The mosquito plays an essential role in theheartworm's life cycle since it is required as an intermediate host.Adult female heartworms living in an infected host give birth to larvaecalled microfilaria, which can circulate in the bloodstream for as longas two years and are ingested by bloodsucking mosquitos. When a mosquitobites and takes up blood from such an infected host, it picks up saidmicrofilaria, which start to develop in the mosquito such that the firstand second larval stages (L₁) and (L₂) of the heartworm developmentoccurs within the body of a mosquito. Once said larvae have matured intothe third larval stage (L₃), the infective larval stage, and themosquito locates and bites a host, these infective larvae are depositedonto the surface of the host's skin and enter the new host through themosquito's bite such that they are under the skin at the site of thebite wound. After a short period of about 2 weeks for further growth,they develop into the fourth larval stage (L₄) and migrate to themuscles of the chest and abdomen. 45 to 60 days after infection thelarvae become immature adults (fifth larval stage; L₅) and between 75and 120 days after infection (bite of the mosquito), these immatureheartworms then enter the bloodstream and are carried to the heart andthe pulmonary system, where they significantly increase in size over thenext about three months. By seven months after the infection (bite ofthe mosquito) the adult worms have mated, and the females begin givingbirth to the above-mentioned microfilaria. The matured heartworms canlive for up to about 7 years in dogs and up to about 3 years in cats.Due to the longevity of these worms, each mosquito season can lead to anincreasing number of heartworms in an infected pet.

Due to the extensive use of anthelmintic compounds, a highly resistantworm population is reported to have occurred. The occurrence of thisresistance against known anthelmintics is considered to cause growingproblems for a successful treatment of the above-mentioned disease(s).

WO 2018/087036 A1 and WO 2019/025341 A1 both disclose a compoundconsidered as anthelmintic, namely a quinoline 3-carboxamide derivativeof the following structure

-   -   wherein residues R¹, R², R³, R⁴, R⁵, R⁶, A and Q are defined        correspondingly.

Further, WO 2017/178416 discloses a compound considered as anthelmintic,namely a pyrazolopyrimidine derivative of the following structure

-   -   wherein residues R⁰, R¹, R², R³, R⁴, Q, X and Y as well as        variable n are defined correspondingly.

The molecules are considered as modulators of the calcium-activatedpotassium channel slo-1 of nematodes, wherein slo-1 can be regarded asthe helminth's ortholog of the human KCa1.1 channel (potassiumcalcium-activated channel subfamily M alpha 1), which is encoded by theKCNMA1 gene (KCa1.1 and KCNMA1 are often used synonymously). Slo-1exhibits calcium-activated potassium channel activity and voltage-gatedpotassium channel activity. Slo-1 channels play an important role in theneuromuscular system as well as in secretory cells among others. Thus,slo-1 modulators are reported to be involved in several processesincluding behavioural response to ethanol, locomotion and pharyngealpumping. More particularly they disrupt neuromuscular transmissioncausing a flaccid paralysis and also affect feeding and egg-laying.Further, they slow the development of the larvae and the adults of thecorresponding helminth.

Nevertheless, especially in view of the occurrence of resistance toknown anthelmintic compounds there is still an urgent need for newactive pharmaceutical ingredients that are able to address infections byhelminths.

Hence, it is an object of the present invention to overcome one or moreof the drawbacks of the prior art.

It is an object to provide new anthelmintic compounds which can be usedto address infections in mammals, in particular in pets such as cats anddogs, especially in dogs. In particular, it is an object to provide newanthelmintic compounds which can be used to address infections inmammals by parasitic helminths such Ostertagia ostertagi, Cooperiaoncophora, Cooperia punctata, Trichostrongylus axei, Haemonchus placei,Haemonchus contortus, Nematodirus helvetianus, Nematodirus spathiger,Trichostrongylus colubriformis, Trichostrongylus circumcincta,Oesophagostomum venulosum, Chabertia ovina, Dictyocaulus viviparous,Dictyocaulus filaria, Dirofilaria immitis, Dirofilaria repens; b)Trematodes: Fasciola hepatica, Fascioloides magna, Dicrocoeliumdentriticum, Paramphistomum cervi, c) Cestodes: Monezia expansa, inparticular infections by Dirofilaria immitis (heartworm).

Another object is to provide new anthelmintic compounds which can beused to address infections in mammals, wherein these compounds arecompatible with standard antiparasitic treatments in pets, in particularin cats and dogs, especially in dogs. In particular, it is an object toprovide new anthelmintic compounds which can be used to addressinfections in pets such as cats and dogs and which can be administeredorally or topically.

More specifically, it is an object to provide new anthelmintic compoundswhich can be used to address infections in mammals by parasitichelminths, in particular infections by Dirofilaria immitis (heartworm),but does not negatively affect the host by undesired side-effects.

Moreover, it is an object that said new anthelmintic compounds can beused in different treatment schedules, in particular in monthly orlonger treatment schedules.

SUMMARY OF THE INVENTION

Surprisingly it was found that at least one of the objects can be met byproviding a compound according to Formula (I)

-   -   wherein    -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR²R³, COOH, C(═O)OR⁴, SR⁴, SOR⁴, SO₂R⁴, SO₂NR⁵R⁶            and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, NR^(2′)R^(3′),                    C(═O)OR^(4′), SR^(4′), SOR^(4′), SO₂R^(4′),                    SO₂NR^(5′)R^(6′) and C(═O)NR^(5′)R^(6′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R² and R³            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(2″)R^(3″), C(═O)OR^(4″), SR^(4″), SOR⁴, SO₂R^(4″),                SO₂NR^(5″)R^(6″) and C(═O)NR^(5″)R^(6″),    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(2′), R^(3′), R^(4′), R^(5′) and R^(6′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(2″), R^(3″), R^(4″), R^(5″) and R^(6″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR⁸R⁹, COOH, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰,            SO₂NR¹¹R¹² and C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, oxo, NR^(8′)R^(9′),                    C(═O)OR^(10′), SR^(10′), SOR^(10′), SO₂R^(10′),                    SO₂NR^(11′)R^(12′) and C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(8″)R^(9″), C(═O)OR^(10″), SR^(10″), SOR^(10″),                SO₂R^(10″), SO₂NR^(11″)R^(12″) and C(═O)NR^(11″)R^(12″),    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R¹³ is hydrogen or C₁₋₃ alkyl,    -   R¹⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, NR^(14′)R^(14″),        wherein R^(14′) and R^(14″) are independently C₁₋₃-alkyl or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16′), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   R¹⁹ is independently selected from the group consisting of        C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5- to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered                heteroaryl, C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen,                cyano, nitro, hydroxy, mercapto, NR²⁰R²¹, C(═O)OR²²,                SR²², SOR²², SO₂R²², SO₂NR²³R²⁴ and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to            10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁-C₆-alkyl            substituted with C₆₋₁₀-aryl, C₁₋₆-alkyl substituted with 5-            to 10-membered heteroaryl, or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5-            to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered            heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto or the            heterocyclic ring formed by R²⁰ and R²¹ together with the N            atom to which they are attached is optionally substituted            with one or more substituents independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(20′)R^(21′), C(═O)OR^(22′) SR²², SOR^(22′),                SO₂R^(22′), SO₂NR^(23′)R^(24′), and                C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R²⁵ is independently selected from hydrogen and C₁₋₆-alkyl,    -   or a stereoisomer, physiologically acceptable salt, ester,        solvate, polymorph, prodrug and mixtures thereof.

In one embodiment of the invention and/or embodiments thereof, R¹ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,        hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituents independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy                and NR^(2′)R^(3′),

-   R² and R³ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀ aryl and 5 to        10-membered heteroaryl, or

-   R² and R³ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3 further    ring atoms are selected from N, S and O,    -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5 to        10-membered heteroaryl or the heterocyclic ring formed by R² and        R³ together with the N atom to which they are attached is        optionally substituted with one or more substituent(s)        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,

-   R⁴, R⁵ and R⁶ are independently selected from hydrogen and    C₁₋₆-alkyl,

-   R^(2′) and R^(3′) are independently selected from hydrogen and    C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof, R¹ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy and halogen,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy and                NR^(2′)R^(3′),    -   wherein R^(2′) and R^(3′) are independently selected from        hydrogen and C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof, R¹ isindependently selected from the group consisting of

-   -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,        fluoride and chloride, in particular hydrogen and methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4- to            10 membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4- to 10 membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10 membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)R^(10′), and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to 10            membered heterocyclyl and 5- to 10 membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to            10 membered heterocyclyl, and 5- to 10 membered heteroaryl            or the heterocyclic ring formed by R⁸ and R⁹ together with            the N atom to which they are attached is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)—OR^(10″) and C(═O)NR^(11″) R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl, C₁₋₆-alkoxy, hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰,            SOR¹⁰, SO₂R¹⁰ and C(═O)NR¹¹R¹²,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered                heterocyclyl or C₁₋₆-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₆-alkyl, 5- to 10 membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, and 5-            to 10 membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, and 5-            to 10 membered heteroaryl or the heterocyclic ring formed by            R⁸ and R⁹ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″),    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen or        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₆-alkyl.    -   R^(8″) are R^(9″) are independently selected from hydrogen or        C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

In one embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, hydroxyethylamino,        2-hydroxyethylmethylamino methoxyethylamino, cyclopropylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(16′)R¹⁶, wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is CR¹⁵ wherein R¹⁵ is independently hydrogen, halogen C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(5′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen, C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is CR¹⁷, wherein R¹⁷ is hydrogen,    -   A4 is CR¹⁸, wherein R¹⁸ is hydrogen.

In one embodiment of the invention and/or embodiments thereof, none, oneor two of residues A1, A2, A3 and A4 is N.

In one embodiment of the invention and/or embodiments thereof, R¹⁹ isindependently selected from the group consisting of

-   -   C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered                heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy, NR²⁰R²¹,                C(═O)OR²² and C(═O)NR²³R²⁴,

-   R²⁰ and R²¹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or

-   R²⁰ and R²¹ together with the N atom to which they are attached form    a saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 0, 1, 2, or 3 further ring atoms are selected from N,    S and O;    -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₁₀-cycloalkyl or        C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹        together with the N atom to which they are attached is        optionally substituted with one or more substituents        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered            heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy, halogen, cyano, hydroxy, NR^(20′)R^(21′),            C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′)

-   R²², R²³ and R²⁴ are independently selected from hydrogen and    C₁₋₆-alkyl,

-   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently    selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof, R¹⁹ isindependently selected from the group consisting of

-   -   C₆₋₁₀-aryl and 5- to 10-membered heteroaryl        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,            -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                substituted with one or more substituents independently                selected from the group consisting of halogen, cyano,                hydroxy preferably each C₁₋₆-alkyl, C₁₋₆-alkoxy, is                optionally substituted with one or more halogen.

In one embodiment of the invention and/or embodiments thereof, R¹⁹ isC₆₋₁₀-aryl,

-   -   wherein the C₆₋₁₀-aryl is optionally substituted with one or        more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl, halogen, cyano and nitro, wherein each            C₁₋₆-alkyl, is optionally substituted with one or more            halogen.

In one embodiment of the invention and/or embodiments thereof, R¹⁹ isC₆₋₁₀-aryl,

-   -   wherein the C₆₋₁₀-aryl is phenyl substituted with one, two or        three substituents independently selected from the group        consisting of        -   fluoride, chloride bromide, trifluoromethoxy and            trifluoromethyl.

In one embodiment of the invention and/or embodiments thereof, R²⁵ ishydrogen.

In one embodiment of the invention and/or embodiments thereof thecompound according to Formula (I) is present in form of the(S)-enantiomer.

Further, the present invention provides a process for preparing thecompound according to Formula (I) comprising the step of

-   -   reacting a compound of Formula (A)

-   -   with a compound of Formula (B)

wherein R¹, R⁷, R¹³, R¹⁴, A1, A2, A3, A4, R¹⁹ and R²⁵ are defined as inany one of the embodiments as described herein,to obtain the compound according to Formula (I).

Further, the present invention provides a veterinary compositioncomprising

-   -   compound according to Formula (I) as defined as in any one of        the embodiments as described herein, and    -   one or more physiologically acceptable excipient(s).

In one embodiment of the invention and/or embodiments thereof, the oneor more physiologically acceptable excipient(s) are selected fromcarriers, fillers, flavours, binders, antioxidants, buffers, sugarcomponents, lubricants, surfactants, stabilizers, flow agents,disintegration agents and preservatives and mixtures thereof.

Further, the present invention provides compounds according to Formula(I) as defined as in any one of the embodiments as described herein orthe veterinary composition according to the invention for use as amedicament.

Further, the present invention provides compounds according to Formula(I) or the veterinary composition according to the invention for use inthe treatment of disorders/diseases caused by helminths.

In one embodiment of the invention and/or embodiments thereof, thedisease is the heartworm disease.

In one embodiment of the invention and/or embodiments thereof, thehelminths are Dirofilaria immitis.

DETAILED DESCRIPTION

It was found that compounds according to Formula (I) or a stereoisomer,physiologically acceptable salt, ester, solvate, polymorph, prodrug andmixtures thereof are useful in the treatment of helminthiasis such asdisorders/diseases caused by helminths such as Ascaridia galli,Haemonchus contortus, Oesophagostomum dentatum and by Dirofilariaimmitis. In particular, the compounds according to the invention and/orany embodiments thereof are useful in the treatment of the heartwormdisease. Optionally, the compounds according to the invention and/or anyembodiments thereof are useful in the treatment of thedisorders/diseases caused by nematodes, in particular Dirofilariaimmitis, wherein the disorder/disease caused by Dirofilaria immitis isthe heartworm disease.

Advantageously the compounds according to the invention and/or anyembodiments thereof are effective against helminth such as Dirofilariaimmitis, but not effective against bacteria that are especially relevantin the mammal's, in particular the dog's, health, such as Acinetobacterbaumannii or Staphylococcus spp. or Streptococcus spp.

The inventors found that the compounds of the invention meet such needsand are therefore very useful in the treatment (and prevention) ofdiseases caused by helminths such as the heartworm disease.

The following abbreviations and definitions are used throughout thisapplication:

Generally, reference to a certain element is meant to include allisotopes of that element. For example, if a group is defined to includehydrogen or a residue is hydrogen, it also includes deuterium andtritium.

The term “C₁₋₆-alkyl” refers to alkyl groups having 1 to 6 carbon atomsthat do not contain heteroatoms. Thus, the term includes straight chainalkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Theterm also includes branched chain isomers of straight chain alkylgroups, including but not limited to, the following that are provided byway of example: —CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —CH(CH₂CH₃)₂, —C(CH₃)₃,—CH₂CH(CH₃)₂, —CH₂CH(CH₂CH₃)₂, —CH₂C(CH₃)₃, —CH(CH₃)CH(CH₃)(CH₂CH₃),—CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH(CH₃)(CH₂CH₃), —CH₂CH₂C(CH₃)₃ and others.Thus, the term “C₁₋₆-alkyl” includes primary alkyl groups having 1 to 6carbon atoms, secondary alkyl groups having 3 to 6 carbon atoms andtertiary alkyl groups having 4 to 6 carbon atoms.

Correspondingly, the term “C₁₋₃-alkyl” refers to alkyl groups having 1to 3 carbon atoms that do not contain heteroatoms. Thus, the termincludes straight chain alkyl groups such as methyl, ethyl, and propyl.The term also includes branched chain isomers of straight chain alkylgroups, namely CH(CH₃)₂. Thus, the term “C₁₋₃-alkyl’ includes primaryalkyl groups having 1 to 3 carbon atoms, and a secondary alkyl groupshaving 3 carbon atoms.

The term “C₂₋₆-alkenyl” refers to straight and branched chain alkenylgroups such as those described with respect to the “C₂₋₆-alkyl” definedabove, except that at least one double bond exists between two carbonatoms. Examples include, but are not limited to —CH═CH₂, —C(CH₃)═CH₂,—CH═CH(CH₃), —CH═C(CH₃)₂, —CH═CH(CH₃), —C(CH₃)═CH(CH₃), —C(CH₂CH₃)H═CH₂,—CH₂═CH(CH₂CH₃), —CH₂CH₂—CH═CH₂, CH₂CH₂—C(CH₃)═CH₂, CH₂CH₂—CH═C(CH₃)H,—CH═CH—(CH₂)₂CH₃, —CH═C(CH₃)—CH₂CH₃, —(CH₂)₃—CH═CH₂, —(CH₂)₄—CH═CH₂,—(CH₂)₂—CH═C(CH₃)₂, butadienyl, pentadienyl, and hexadienyl amongothers.

The term “C₂₋₆-alkynyl” refers to straight and branched chain alkynylgroups such as those described with respect to the “C₂₋₆-alkyl” definedabove, except that at least one triple bond exists between two carbonatoms. Examples include, but are not limited to, — to —C≡CH, —C≡CCH₃,—C≡C—CH₂CH₃, —CH₂—C≡CH, —CH(CH₃)—C≡CH, —C(CH₃)₂—C≡CH, —CH₂—C≡CCH₃,—CH(CH₃)—C≡CCH₃, —C(CH₃)₂—C≡CCH₃, —CH₂—C≡C—CH₂CH₃, —CH(CH₃)—C≡C—CH₂CH₃,—C(CH₃)₂—C≡C—CH₂CH₃, —(CH₂)₂—C≡C—CH₂CH₃, —(CH₂)₃—C≡C—CH₃ among others.

The term “C₃₋₁₀-cycloalkyl” refers to non-aromatic monocyclic alkylgroups having 3 to 10 carbon atoms or non-aromatic polycyclic alkylgroups having 3 to 10 carbons atoms, wherein said groups consist solelyof carbon and hydrogen atoms. Cycloalkyl may include fused or bridgedring systems having 3 to 10 carbon atoms. Non-aromatic monocyclic alkylgroups having 3 to 10 carbon atoms include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like. Non-aromatic polycyclic alkyl groups having 3to 10 carbon atoms include, but are not limited to, adamantine,norbornane, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like.

The term “5 to 10-membered heterocyclyl” refers to cyclic groups wherein5 to 10 members (atoms) form the skeleton, wherein the skeleton of saidcyclic compounds comprises at least one carbon atom and at least oneheteroatom. Examples of heteroatoms include, but are not limited to, N,O and S. Unless specifically stated otherwise in the specification, the“5 to 10-membered heterocyclyl” may be a monocyclic, bicyclic orpolycyclic group which may include fused or bridged ring systems,wherein a part of the fused ring system may be aromatic; the nitrogen,carbon or sulphur atoms in the “5 to 10-membered heterocyclyl” may beoptionally oxidized; the nitrogen atom may be optionally quaternized,and the heterocyclyl residue radical may be partially saturated.

Examples of heterocyclyl groups include, but are not limited, topyrrolinyl, 3H-pyrazolyl, 4H-pyrazolyl dihydropyridyl, pyrrolidinyl,imidazolidinyl, piperidinyl, piperazinyl, homopiperazinyl, indolinyl,quinuclidinyl, morpholinyl, thiomorpholinyl thiazolodinyl,dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene,tetrahydrothiopyran, benzothiazinyl such as 2H-1,4-benzothiazinyl,dihydrobenzothiazinyl such a 2H-3,4-dihydrobenzothiazinyl, benzodioxolylsuch as 1,3-benzodioxoyl, dihydrooxathiinyl, 1,4-oxathianyl. Furtherexamples of heterocyclyl groups include, but are not limited to, thosedescribed above in which one or more S atoms in the ring isdouble-bonded to one or two oxygen atoms (sulfoxides and sulfones) suchas tetrahydrothiophene, tetrahydrothiophene oxide andtetrahydrothiophene-1,1-dioxid as well as thiomorpholine, thiomorpholineoxide and thiomorpholine-1,1 dioxide.

The term “C₆₋₁₀ aryl” refers to a group with an aromatic skeletalstructure, wherein the ring atoms of the aromatic skeletal structure arecarbon atoms. In other words, the “C₆₋₁₀ aryl” does not containheteroatoms such as N, S, O in the aromatic skeletal structure.

Examples for aryl groups include, but are not limited, to phenyl,biphenyl and naphthyl.

The term “5 to 10-membered heteroaryl” refers to an aromatic groupwherein 5 to 10 members (atoms) form the skeleton, wherein the skeletonof said cyclic compound comprises at least one carbon atom and at leastone heteroatom. Examples of heteroatoms include, but are not limited to,N, O and S. Unless specifically stated otherwise in the specification,the “5 to 10-membered heterocyclyl” may be a monocyclic or bicyclic orpolycyclic group, which may include fused ring systems.

Examples of 5 to 10-membered heteroaryl groups include, but are notlimited to, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl such as 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl,1H-1,2,4-triazolyl and 4H-1,2,4-triazlyl, tetrazolylsuch as 1H-tetrazolyl, 2H tetrazolyl and 5H-tetrazoyl, indolyl,isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, naphthyridinyl, benzotriazolyl, oxazolyl,isoxazolyl, oxadiazolyl such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, benzoxazolyl, benzoxadiazolyl, benzoxazinyl such as2H-1,4-benzoxazinyl thiazolyl, isothiazolyl, thiadiazolyl such1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, thienyl, benzothiazolyl, benzothiadiazolyl,benzothiazinyl, benzofuranyl, quinolinyl, isoquinolin, cinnolinyl,quinaxolinyl quinoxalinyl, triazinyl, tetrazinyl, purinyl, pteridinyl,furyl, benzodioxolyl such as 1,3-benzodioxoyl, benzothienyl,benzodithiinyl and benzoxathiinyl.

The term “C₁₋₆-alkoxy” refers to a group which based on an alkyl grouphaving 1 to 6 carbon atoms bound to an oxygen. The alkyl group having 1to 6 carbon atoms refers to straight and branched chains such as thosedescribed with respect to the “C₁₋₆-alkyl” defined above.

Correspondingly, the term “C₁₋₃-alkoxy” refers to a group which is basedon an alkyl group having 1 to 3 carbon atoms bound to an oxygen. Thealkyl group having 1 to 3 carbon atoms refers to straight and branchedchains such as those described with respect to the “C₁₋₃-alkyl” definedabove.

The term “C₁₋₆-alkylmercapto” refers to a group which is based on analkyl group having 1 to 6 carbon atoms bound to a sulfur The alkyl grouphaving 1 to 6 carbon atoms refers to straight and branched chains suchas those described with respect to the “C₁₋₆-alkyl” defined above.

“Optionally substituted” refers to the optional replacement of one ormore hydrogen(s) of the group to be substituted with one or more of thedefined substituent(s).

Further amines, hydroxyl and mercapto groups may be protected. The term“protected” with regard to these groups refers to forms of thesefunctionalities with a protecting group to prevent said groups fromundesirable reaction. Such protecting groups are known to those skilledin the art for example from Protective Groups in Organic Synthesis;Wuts, P. G. M. John Wiley & Sons, New York, NY, (53^(th) Edition, 2014).The protecting groups can be added or removed using the procedures setforth therein.

Examples of protected hydroxyl groups include, but are not limited to,silyl ethers such as those obtained by reaction of a hydroxyl group witha reagent such as, but not limited to, t-butyldimethyl-chlorosilane,trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane;substituted methyl and ethyl ethers such as, but not limited to,methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether,t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranylethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as,but not limited to, benzoylformate, formate, acetate, trichloroacetateand trifluoracetate.

Examples of protected amine groups include, but are not limited to,amides such as formamide, acetamide, trifluoroacetamide and benzamide;imides, such as phthalimide and dithiosuccinimide; carbamate such astert-butyloxycarbonyl (Boc) and others.

Examples of protected mercapto groups include, but are not limited to,thioether such as S-benzyl thioether, and S-4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals and others.

Stereoisomers include compounds which are made of the same atomsconnected in the same sequence, but the atoms are positioned differentlyin space. Stereoisomers include diastereoisomers and enantiomers.

A “physiologically acceptable salt” it referred to as salt with aninorganic base, organic base, inorganic acid, organic acid or basic oracidic amino acid.

Examples of suitable inorganic acids for making (physiologicallyacceptable) salts include, but are not limited to, hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.

Examples of suitable organic acids for making (pharmaceuticallyacceptable) salts include, but are not limited to, cholic acid, sorbicacid, lauric acid, acetic acid, trifluoroacetic acid, formic acid,propionic acid, succinic acid, glycolic acid, gluconic acid, digluconicacid, lactic acid, malic acid, tartaric acid, citric acid, ascorbicacid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, asparticacid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid,stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid,mandelic acid, embonic acid, ethanesulfonic acid, benzenesulfonic acid,toluene sulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid,sulfanilic acid, cyclohexylaminosulfonic acid, β-hydroxybutyric acid,galactaric acid, galacturonic acid, adipic acid, alginic acid, butyricacid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,dodecylsulficacid, glycoheptanoic acid, glycerophosphic acid, heptanoicacid, hexanoic acid, nicotinic acid, 2-naphthalesulfonic acid, oxalicacid, palmoic acid, pectinic acid, 3-phenylpropionic acid, picric acid,pivalic acid, thiocyanic acid, tosylic acid, undecanoic acid and acidicamino acids such as aspartic acid and glutamic acid.

Examples of base addition salts may include, for example, metallic saltsand organic salts.

Metallic salts include, but are not limited to, alkali metal (group Ia)salts, alkaline earth metal (group IIa) salts and other physiologicallyacceptable metal salts. Examples of such salts may be made fromaluminium, calcium, lithium, magnesium, potassium, sodium, and zinc. Forexample, a free acid compound may be mixed with sodium hydroxide to formsuch a base addition salt.

Organic salts may be made from amines, such as trimethylamine,diethylamine, N,N′-dibenzyl-ethylenediamine, chloroprocaine,ethanolamine, diethanolamine, ethylenediamine, N-methyl-glucamine,procaine and basic amino acids such as arginine, lysine and ornithine.

As used herein, the term “pharmaceutically acceptable ester” refers toesters that hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Representative examples of particular esters include, but are notlimited to, formates, acetates, propionates, butyrates, acrylates andethylsuccinates.

A solvate of a compound can be regarded as a compound in which anorganic solvent or water adheres to said compound. Organic solventsrefer to the ones which are known by the skilled person. In case thatwater is adhered to the compound the corresponding compound is known asa hydrate.

The term “polymorph” as used herein and as generally understood by theskilled person refers to different crystalline forms of the samemolecular entity. Therefore, due to their different chemicalcompositions, solvates and hydrates as discussed above are not includedin the definition of polymorphism but are rather designated“pseudopolymorphs” instead.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above Formula ((I), for exampleby hydrolysis in blood. A thorough discussion is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C.S. Symposium Series, and in Edward B. Roche, Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, commensurate with areasonable benefit/risk ratio and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ is defined as below.

In an embodiment of the invention and/or embodiments thereof, R¹ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,        hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituents independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy                and NR^(2′)R^(3′),

-   R² and R³ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to        10-membered heteroaryl, or

-   R² and R³ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3 further    ring atoms are selected from N, S and O;    -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5 to        10-membered heteroaryl or the heterocyclic ring formed by R² and        R³ together with the N atom to which they are attached is        optionally substituted with one or more substituent(s)        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,

-   R⁴, R⁵ and R⁶ are independently selected from hydrogen and    C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,

-   R^(2′) and R^(3′) are independently selected from hydrogen and    C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R¹ is independently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and        C(═O)NR⁵R⁶,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituents independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy                and NR^(2′)R^(3′),

-   R⁵ and R⁶ are independently selected from hydrogen and C₁₋₃-alkyl,

-   R^(2′) and R^(3′) are independently selected from hydrogen and    C₁₋₃-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof, R¹ is independently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy and halogen,        -   wherein C₁₋₆-alkyl and C₁₋₆-alkoxy is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy and                NR^(2′)R^(3′),

-   wherein R^(2′) and R^(3′) are independently selected from hydrogen    and C₁₋₃-alkyl, more preferably from hydrogen and methyl.

In one embodiment of the invention and/or embodiments thereof, R¹ isindependently selected from the group consisting of

-   -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,        fluoride and chloride, in particular hydrogen and methyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iai), (Iaii), (Iaiii) or (Iaiv)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷, R¹³, R¹⁴, A1, A2,A3, A4, R¹⁹ and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iai), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iaii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iaiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iaiv), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷ is defined as below.

In an embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to        10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,        NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and C(═O)NR^(1″)R¹²        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4            to 10-membered heterocyclyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR^(11′)R^(12′),

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to        10-membered heterocyclyl and 5 to 10-membered heteroaryl, or

-   R⁸ and R⁹ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further    ring atoms are selected from N, S and O;    -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to        10-membered heterocyclyl or 5 to 10-membered heteroaryl or the        heterocyclic ring formed by R⁸ and R⁹ together with the N atom        to which they are attached is optionally substituted with one or        more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,            NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);

-   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and    C₁₋₆-alkyl,

-   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently    selected from hydrogen and C₁₋₆-alkyl,

-   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently    selected from hydrogen and C₁₋₆-alkyl.

In an embodiment of the invention and/or embodiments thereof, wherein R⁷is independently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered        heterocyclyl, C₁₋₆-alkoxy, hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰,        SOR¹⁰, SO₂R¹⁰ and C(═O)NR¹¹R¹²,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10-membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₆-alkyl, 5 to 10-membered heterocyclyl, C₁₋₆-alkoxy,                halogen, cyano, hydroxy, oxo, NR^(8′)R^(9′),                C(═O)OR^(10′) and C(═O)NR^(11′)R^(12′),

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to        10-membered heteroaryl, or

-   R⁸ and R⁹ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further    ring atoms are selected from N, S and O;    -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5 to        10-membered heteroaryl or the heterocyclic ring formed by R⁸ and        R⁹ together with the N atom to which they are attached is        optionally substituted with one or more substituent(s)        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);

-   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen or    C₁₋₆-alkyl, preferably from hydrogen or C₁₋₃-alkyl,

-   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently    selected from hydrogen or C₁₋₆-alkyl, preferably from hydrogen or    C₁₋₃-alkyl,

-   R^(8″) and R^(9″) are independently selected from hydrogen or    C₁₋₆-alkyl, preferably from hydrogen or C₁₋₃-alkyl.

In an embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered        heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and        SO₂R¹⁰,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl or C₁₋₃-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl, C₁₋₆-alkoxy,                halogen, cyano, hydroxy, oxo, NR^(8′)R^(9′),                C(═O)OR^(10′) and C(═O)NR^(11′)R^(12′),

-   R⁸ and R⁹ are independently selected from the group consisting of    hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to    10-membered heteroaryl, or R⁸ and R⁹ together with the N atom to    which they are attached form a saturated or unsaturated heterocyclic    ring having 3 to 12 ring atoms, wherein 1 ring atom is N and wherein    0, 1, 2, or 3 further ring atoms are selected from N, S and O;    -   wherein the C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl or 5 to        10-membered heteroaryl or the heterocyclic ring formed by R⁸ and        R⁹ together with the N atom to which they are attached is        optionally substituted with one or more substituent(s)        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);

-   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,    preferably from hydrogen, methyl or ethyl,

-   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently    selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,    methyl or ethyl,

-   R^(8″) and R^(9″) are independently selected from hydrogen or    C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl.

In an embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

In an embodiment of the invention and/or embodiments thereof, R⁷ isindependently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, hydroxyethylamino,        2-hydroxyethylmethylamino, methoxyethylamino, cyclopropylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl,    -   azetidin-1-yl, tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl, in particular dimethylamino and        morphilin-4-yl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ibi), (Ibii), (Ibiii), (Ibiv), (Ibv)or (Ibvi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R₁, R¹³, R¹⁴, A1, A2,A3, A4, R¹⁹ and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ibi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ibii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ibiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ibiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ibv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ibvi), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹³ and R¹⁴ as well as A1, A2, A3 and A4are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹³ is hydrogen or C₁₋₃ alkyl and    -   R¹⁴ is hydrogen, C₁₋₃ alkyl or C₁₋₃ alkoxy,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

More suitably, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹³ is hydrogen or C₁₋₃ alkyl and    -   R¹⁴ is hydrogen or C₁₋₃ alkyl    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl, C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl, C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl, C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl, C₁₋₃ alkoxy,    -   wherein none, one or two of residues A1, A2, A3 and A4 is N.

More suitably, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹³ is hydrogen, methyl or ethyl, preferably hydrogen or methyl        and    -   R¹⁴ is hydrogen or methyl, preferably hydrogen    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkyl,    -   wherein none, one or two of residues A1, A2, A3 and A4 is N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ici).

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ici), preferably in form of the(S)-enantiomer.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—.

Examples of the 5 or 6 carbon atoms containing saturated or unsaturatedrings, wherein the 5 or 6-carbon atoms containing saturated ring isoptionally substituted with one or more C₁₋₃-alkyl or ═O, and whereinone or more of the saturated ring forming carbon atoms are optionallyreplaced by —NH—, —N═, N—, —O—, —S(O)—, —S(O)₂— or —S—, — and examplesof the 5 or 6-carbon atoms containing unsaturated or unsaturated rings,wherein the 5 or 6-carbon atoms containing saturated ring is optionallysubstituted with one or more C₁₋₃-alkyl, and wherein one or more of theunsaturated ring forming carbon atoms are optionally replaced by —NH—,—N═, N—, —O—, — or —S—, — include, but are not limited to, the residueswhich are represented by the below structures

-   -   wherein    -   denotes the bond to the amide group; and    -   denotes the bond with which the above ring system is fused with        the aromatic ring inter alia comprising A1, A2, A3 and A4.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Icii), (Iciii), (Iciv) or (Icv)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Icii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iciii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iciv),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Icy), preferably in form of the (S)-enantiomer.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In an embodiment of the invention and/or embodiments thereof

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Icvi), (Icvii) or (Icviii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Icvi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Icvii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Icviii),preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹⁹ is defined as below.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy, C(═O)OR²², SO₂R²², SO₂NR²³R²⁴ and                    C(═O)NR²³R²⁴, wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy,                    is optionally substituted with one or more                    substituents independently selected from the group                    consisting of halogen, cyano, hydroxy, preferably                    each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more halogen,    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from the group consisting of        C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                C(═O)OR²² and C(═O)NR²³R²⁴, wherein each C₁₋₆-alkyl,                C₁₋₆-alkoxy, is optionally substituted with one or more                substituents independently selected from the group                consisting of halogen, cyano, hydroxy, preferably each                C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally substituted with                one or more halogen    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl        -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy, wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is                optionally substituted with one or more substituents                independently selected from the group consisting of                halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                C₁₋₆-alkoxy, is optionally substituted with one or more                halogen.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ is a 5to 10-membered heteroaryl

-   -   wherein the 5 to 10-membered heteroaryl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano and nitro and            hydroxy, wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally            substituted with one or more substituents independently            selected from the group consisting of halogen, cyano,            hydroxy, preferably each C₁₋₆-alkyl, C₁₋₆-alkoxy, is            optionally substituted with one or more halogen.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ is a 5to 10-membered heteroaryl

-   -   wherein the 5 to 10-membered heteroaryl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl optionally substituted with one or more halogen            and halogen, preferably halogen.

Examples of 5 to 10-membered heteroaryl groups include, but are notlimited to, pyrrolyl, imidazolyl, pyrazolyl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrazinyl,pyridazinyl, triazolyl such as 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl,1H-1,2,4-triazolyl and 4H-1,2,4-triazlyl, tetrazolylsuch as 1H-tetrazolyl, 2H tetrazolyl and 5H-tetrazoyl, indolyl,isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinoline 4-yl,quinoline-8-yl, isoquinolyl, indazolyl, naphthyridinyl, benzotriazolyl,oxazolyl, isoxazolyl, oxadiazolyl such as 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl, benzoxazolyl, benzoxadiazolyl,benzoxazinyl such as 2H-1,4-benzoxazinyl, thiazolyl, isothiazolyl,thiadiazolyl such 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl and 1,2,5-thiadiazolyl, thien-2-yl, thien-3-ylbenzothiazolyl, benzothiadiazolyl, benzothiazinyl, benzofuranyl,quinolinyl, isoquinolinyl, cinnolinyl, quinaxolinyl, quinoxalinyl,triazinyl, tetrazinyl, purinyl, pteridinyl, furyl, benzodioxolyl such as1,3-benzodioxoyl, benzothienyl, benzodithiinyl and benzoxathiinyl.Preferred are pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl,pyrimidin-3-yl, pyrimidin-4-yl, quinoline-8-yl, thien-2-yl andthien-3-yl.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ is a 5to 10-membered heteroaryl,

-   -   wherein the 5 to 10-membered heteroaryl is substituted with one        or more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl optionally substituted with one or more halogen            and halogen, preferably halogen.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ isselected from the group consisting of

-   -   2,5-dichloropyridin-4-yl, 2,6-dichloropyridn-4-yl,        5-chlorothien-2-yl, 5-chlorothien-3-yl and        2,6-difluoropyridin-yl.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ isselected from the group consisting of

-   -   3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, whereinR¹⁹ is C₆₋₁₀-aryl,

-   -   wherein the C₆₋₁₀ aryl is optionally substituted with one or        more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano and nitro wherein            each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally substituted with            one or more substituents independently selected from the            group consisting of halogen, cyano, hydroxy, preferably each            C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally substituted with one            or more halogen.

In an embodiment of the invention and/or embodiments thereof, whereinR¹⁹ is C₆₋₁₀-aryl,

-   -   wherein C₆₋₁₀ aryl is phenyl substituted with one, two or three        substituents independently selected from the group consisting of        fluoride, chloride bromide, trifluoromethyl and        trifluoromethoxy.

Examples of phenyl substituted with one, two or three substituentsindependently selected from the group consisting of

-   -   fluoride, chloride, bromide, methyl, methoxy, dimethylamine,        trifluoromethyl and trifluoromethoxy include, but are not        limited to, 2-fluorophenyl, 3-fluourophenyl, 4-fluorophenyl,        2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,        3-bromophenyl, 4-bromophenyl, 2,3-difluorophenyl,        2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl,        3,5-difluorophenyl, 2,6-difluorophenyl, 2,3-dichlorophenyl,        2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl,        3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl,        2,5-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl,        2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl,        3,4,5-trifluorophenyl, 2,3,4-trichlorophenyl,        2,3,5-trichlorophenyl, 3,4,5-trichlorophenyl,        2,3,4-tribromophenyl, 2,3,5-tribromophenyl,        3,4,5-tribromophenyl, 2-chloro-3-fluorophenyl,        2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl,        3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl,        3-chloro-5-fluorophenyl, 3-chloro-6-fluorophenyl,        4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl,        4-chloro-5-fluorophenyl, 5-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 5-chloro-4-fluorophenyl,        3-bromo-2-fluorophenyl, 3-bromo-5-fluorophenyl,        3-bromo-6-fluorophenyl, 4-bromo-2-chlorophenyl,        4-bromo-3-chlorophenyl, 3,4-dichloro-2-fluoro-phenyl,        3,5-dichloro-2-fluorophenyl, 3,5-dichloro-4-fluorophenyl,        4,5-dichloro-3-flurorophenyl, 3,4-dibromo-2-fluoro-phenyl,        3,5-dibromo-2-fluorophenyl, 4,5-dibromo-3-flurophenyl,        2-chloro-3,4-difluorophenyl, 2-chloro-3,5-difluorophenyl,        3-chloro-4,5-difluorophenyl, 3-chloro-5-6-difluorophenyl,        3,4-dibromo-2-chlorophenyl, 3,5-dibromo-2-chlorophenyl,        4,5-dibromo-3-chlorophenyl, 2-bromo-3,4-difluorophenyl,        2-bromo-3,5-difluorophenyl, 3-bromo-4,5-difluorophenyl,        2-bromo-3,4-dichlorophenyl, 2-bromo-3,5-dichlorophenyl,        3-bromo-4,5-dichlorophenyl, 4-bromo-3-chloro-2-fluorophenyl,        4-bromo-2-chloro-3-fluorophenyl,        2-bromo-3-chloro-4-fluorophenyl,        5-bromo-3-chloro-2-fluorophenyl,        5-bromo-2-chloro-3-fluorophenyl,        2-bromo-3-chloro-5-fluourophenyl,        5-bromo-4-chloro-3-fluorophenyl,        5-bromo-3-chloro-4-fluorophenyl,        3-bromo-4-chloro-5-fluorophenyl,        2-fluoro-3-chlorophenyl,2-fluoro-5-trifluoromethylphenyl,        2-trifluoromethylphenyl, 3-trifluoromethylphenyl,        3-methoxyphenyl, 2,3-dimethylphenyl, 2-fluoro-5-chlorophenyl,        2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,        3-dimethylaminophenyl, 3-fluoro-5-trifluoromethylphenyl,        2-chloro-5-trifluoromethylphenyl,        2-chloro-3-trifluoromethylphenyl,        3-chloro-5-trifluoromethylphenyl,        3-fluoro-5-trifluoromethylphenyl.

In an embodiment of the invention and/or embodiments thereof, R¹⁹ isindependently selected from 3,5-dichlorophenyl, 2,3-dichlorophenyl,2,3,5-trifluorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,2,3-dimethylphenyl, 3-chlorophenyl, 3-trifluoromethoxyphenyl,3-dimethylaminophenyl, 3,5-difluorophenyl, 2,3-difluorophenyl,3,4,5-trifluorophenyl, 2-fluoro-3-chlorophenyl,2-fluoro-5-trifluoromethylphenyl, naphth-1-yl, 2-fluoro-5-chlorophenyl,3-fluoro-5-trifluoromethylphenyl, 2,3,5-trichlorophenyl, preferably3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl 3,5-difluorophenyl,2,6-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,3-chloro-5-fluorophenyl, 3-chloro-6-fluorophenyl, 3,4,5-trifluorophenyl,2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl,2-fluoro-3-chlorophenyl, and 2,3,5-trichlorophenyl, more preferably3-chlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,3,5-difluorophenyl, 2,6-difluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-5-fluorophenyl,2-fluoro-3-chlorophenyl, 2,3,5-trichlorophenyl, and3,5-dichloro-4-fluorophenyl, in particular 2,3,5-trifluorophenyl,2,3-dichlorophenyl and 3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Idi), (Idii), (Idiii), (Idiv),(Idv), (Idvi), (Idvii) or (Idviii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷, R¹³, R¹⁴, A1,A2, A3, A4 and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Idi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Idii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Idiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Idiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Idv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Idvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Idvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Idviii), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R²⁵ is defined as below.

In an embodiment of the invention and/or embodiments thereof, R²⁵ ishydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iei) or (Ieii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷, R¹³, R¹⁴, A1,A2, A3, A4 and R¹⁹ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iei), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ieii), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ and R⁷ are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl.    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride.    -   and    -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        hydroxyethylamino, 2-hydroxyethylmethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ifi), (Ifii), (Ifiii), (Ifiv), (Ifv)or (Ifvi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹³, R¹⁴, A1, A2, A3,A4, R¹⁹ and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ifi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ifii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ifiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ifiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ifv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ifvi), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ as well as R¹³, R¹⁴, A1, A2, A3, A4 aredefined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Igi), (Igii) (Igiii), (Igiv), (Igv)or (Igvi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Igi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Igii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Igiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Igiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Igv), preferably in form of the(S)-enantiomer.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Igvi), preferably in form of the(S)-enantiomer.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16′), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,        fluoride and chloride.    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Igvii), (Igiii) (Igix) or (Igx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Igvii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Igviii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Igix),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Igx), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ and R¹⁹ are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀ aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy, wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is                optionally substituted with one or more substituents                independently selected from the group consisting of                halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                C₁₋₆-alkoxy, is optionally substituted with one or more                halogen.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably, 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ihi), (Ihii), (Ihiii), (Ihiv), (Ihv)or (Ihvi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷, R¹³, R¹⁴, A1, A2,A3, A4 and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ihi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ihii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ihiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ihiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ihv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ihvi), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ and R²⁵ are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iii), (Iiii), (Iiiii) or (Iiiv)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷, R¹³, R¹⁴, A1, A2,A3, A4 and R¹⁹ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iiii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iiiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iiiv), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹ is hydrogen.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷ as well as R¹³, R¹⁴, A1, A2, A3 and A4are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered                heterocyclyl or C₁₋₆-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,        and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iji), (Ijii), (Ijiii), (Ijiv),(Ijv), (Ijvi), (Ijvi), (Ijviii) or (Ijix)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iji), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ijii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ijkiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ijiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ijv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ijvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ijvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ijviii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ijix), preferably in form of the(S)-enantiomer.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4            to 10-membered heterocyclyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                NR^(8′)R^(9′), C(═OR^(10′) and C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R¹²″ are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy, wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ijx), (Ijxi), (Ijxii), (Ijxiii),(Ijxiv) or (Ijxv)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R¹⁹ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ijx), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ijxi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ijxii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ijxiii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ijxiv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ijxv), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷ and R¹⁹ are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R¹, C(═O)OR² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2 or 3 further ring atoms are selected        from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR²⁰‘R’,                C(═O)OR^(2′) and C(═O)N^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl, and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iki), (Ikii), (Ikiii), (Ikiv),(Ikv), (Ikvi), (Ikvii), (klviii) or (Ikix)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R¹³ R¹⁴, A1, A2,A3; A4 and R²⁵ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iki), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ikii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ikiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ikiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ikv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ikvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ikvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ikviii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ikix), preferably in form of the(S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷ and R²⁵ are defined as below.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (IIi), (IIii), (IIiii), (IIiv), (IIv)or (IIvi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R¹³ R¹⁴, A1, A2,A3, A4 and R¹⁹ are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (IIi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (IIii), preferably inform of the (S′)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (IIiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (IIiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (IIv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (IIvi), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹³, R¹⁴, A1, A2, A3 and A4 as well as R⁹are defined as below.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy, wherein none, one or two of A1, A2, A3 and        A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Imi), (Imii), (Imiii), (Imiv),(Imv), (Imvi), (Imvii), (Imviii) or (Imix)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Imi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Imii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Imiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Imiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Imv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Imvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Imvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Imviii), preferably in form of the (S)-enantiomer). In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Imix), preferably in form of the(S)-enantiomer.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, nitro, hydroxy, NR²⁰R²¹,                C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Imx), (Imxi), (Imxii), (Imxiii),(Imxiv) or (Imxv)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷ and R²⁵ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Imx), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Imxi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Imxii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Imxiii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Imxiv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Imxv), preferably inform of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹³, R¹⁴, A1, A2, A3 and A4 as well as R²⁵are defined as below.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ini), (Inii), (Iniii), (Iniv), (Inv)or (Invi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷ and R⁹ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ini), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Inii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iniii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iniv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Inv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Invi), preferably inform of the (S)-enantiomer.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R¹⁷ and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18″)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen or        C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Invii), (Inviii), (Inix) or (Inx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷ and R¹⁹ aredefined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Invii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Inviii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Inix),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Inx), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹⁹ and R²⁵ are defined as below.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R²⁴,    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ioi), (Ioii), (Ioiii), (Ioiv), (Iov)or (Iovi)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R⁷ and R¹³, R¹⁴,A1, A2, A3 and A4 are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ioi), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ioii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ioiii),preferably in the form of the (S)-enantiomer). In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ioiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iov), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iovi), preferably inthe form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R⁷ as well as R¹³, R¹⁴, A1, A2, A3 andA4 are defined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ipi), (Ipii), (Ipiii), (Ipiv),(Ipv), (Ipvi), (Ipvii), (Ipviii), (Ipix), (Ipx), (Ipxi) or (Ipxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹⁹ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ipi), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ipii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ipiii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ipiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ipv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ipvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ipvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ipviii), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ipix), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ipx), preferably in theform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ipxi),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ipxii), preferably in the form of the (S)-enantiomer.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R¹²    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy, wherein none, one or two of A1, A2, A3 and A4 are N.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ipxiii), (Ipxiv), (Ipxv), (Ipxvi),(Ipxvii), (Ipxviii), (Ipxix) or (Ipxx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹⁹ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ipxiii), preferably in the form ofthe (S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ipxiv), preferably inthe form of the (S′)-enantiomer. In an embodiment of the inventionand/or embodiments thereof, the compounds are according to Formula((pxv), preferably in the form ofthe (S)-enantiomer. In an embodiment ofthe invention and/or embodiments thereof, the compounds are according toFormula (Ipxvi), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ipxvii), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ipxviii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ipxix),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ipxx), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R⁷ and R¹⁹ are defined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R¹²    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl and        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iqi), (Iqii), (Iqiii), (Iqiv),(Iqv), (Iqvi), (Iqvii) or (Iqviii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹³, R¹⁴, A1, A2, A3,A4 and R²⁵ are defined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iqi), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iqii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iqiii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iqiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iqv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iqvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iqvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iqviii), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R⁷ and R²⁵ are defined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iri), (Irii), (Iriii), (Iriv),(Irv), (Irvi), (Irvii) or (Irviii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹³, R¹⁴, A1, A2, A3,A4 and R¹⁹ are defined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iri), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Irii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iriii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iriv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Irv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Irvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Irvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Irviii), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R¹³, R¹⁴, A1, A2, A3 and A4 are definedas below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16′), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R²⁴    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy, wherein none, one or two of A1, A2, A3 and A4 are N, and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Isi), (Isii), (Isiii), (Isiv),(Isv), (Isvi), (Isvii), (Isviii), (Isix), (Isx), (Isxi) or (Isxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Isi), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Isii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Isiii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Isiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Isv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Isvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Isvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Isviii), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Isix), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Isxv), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Isxi),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Isxii), preferably in the form of the (S)-enantiomer

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more    -   C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2 or 3 further ring atoms are selected        from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R²⁴    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Isxiii), (Ixiv), (Isxv), (Isxvi),(Isxvii), (Isxviii), (Isxix) or (Isxx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Isxiii), preferably in the form ofthe (S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Isxiv), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Isxv),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Isxvi), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Isxvii), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Isxviii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Isxix),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Isxx), preferably in the form of the (S)-enantiomer

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R¹³, R¹⁴, A1, A2, A3, A4 and R²⁵ aredefined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iti), (Itii), (Itiii), (Itiv),(Itv), (Itvi), (Itvii), (Itviii), (Itix), (Itx), (Itxi) or (Itxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷ and R¹⁹ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iti), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Itii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Itiii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Itiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Itv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Itvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Itvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Itviii), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Itix), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Itx), preferably in theform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Itxi),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Itxii), preferably in the form of the (S)-enantiomer.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen,        halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein        R^(18′) and R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Itxiii), (Itxiiii), (Itxv), (Itxvi),(Itxvii), (Itxviii), (Itxix) or (Itxx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷ and R¹⁹ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Itxiii), preferably in the form ofthe (S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Itxiv), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Itxv),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Itxvi), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Itxvii), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Itxviii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Itxix),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Itxx), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R¹⁹ and R²⁵ are defined as below.

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,            hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3        further ring atoms are selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5            to 10-membered heteroaryl or the heterocyclic ring formed by            R² and R³ together with the N atom to which they are            attached is optionally substituted with one or more            substituent(s) independently selected from the group            consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₆-alkyl, preferably from hydrogen and C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy,                5 to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                10-membered heteroaryl, halogen, cyano, nitro, hydroxy,                NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and            C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally                substituted with one or more substituents independently                selected from the group consisting of                -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,                    hydroxy and NR^(2′)R^(3′),    -   R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₃-alkyl,    -   R^(2′) and R^(3′) are independently selected from hydrogen and        C₁₋₃-alkyl,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹ is independently selected from the group consisting of        -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,            fluoride and chloride,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iui), (Iuii), (Iuiii), (Iuiv),(Iuv), (Iuvi), (Iuvii), (Iuviii), (Iuix), (Iux), (Iuxi) or (Iuxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R⁷ and R¹³, R¹⁴, A1,A2, A3, and A4 are defined as in any of the embodiments describedherein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iui), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iuii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iuiii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iuiv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iuv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iuvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iuvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iuviii), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iuix), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iux), preferably in theform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iuxi),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iuxii), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷, R¹³, R¹⁴, A1, A2, A3 and A4 are definedas below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′);    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ivi), (Ivii), (Iviii), (Iviv),(Ivv), (Ivvi), (Ivvii), (Ivviii), (Ivix), (Ivx), (Ivxi) or (Ivxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ivi), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ivii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iviii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iviv), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ivv), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ivvi), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ivvii),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ivviii), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ivix), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ivx), preferably in theform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ivxi),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ivxii), preferably in the form of the (S)-enantiomer.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl, R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are        independently selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18″) and        R^(18″) are independently C₁₋₃-alkyl, and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R¹²    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ivxiii), (Ivxiv), (Ivxv), (Ivxvi),(Ivxvii), (Ivxviii), (Ivxix) or (Ivxx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹ and R²⁵ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ivxiii), preferably in the form ofthe (S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ivxiv), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ivxv),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ivxvi), preferably in the form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ivxvii), preferably in the form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ivxviii), preferably inthe form of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ivxix),preferably in the form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ivxx), preferably in the form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷, R¹³, R¹⁴, A1, A2, A3, A4 and R²⁵ aredefined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R¹²    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iwi), (Iwii), (Iwiii), (Iwiv),(Iwv), (Iwvi), (Iwvii), (Iwviii), (Iwix), (Iwx), (Iwxi) or (Iwxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹ and R¹⁹ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iwi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iwii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iwiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iwiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iwv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iwvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iwvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iwviii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iwix), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iwx), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iwxi),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iwxii), preferably in form of the (S)-enantiomer.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen,        halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein        R^(18″) and R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl, and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl,        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iwxiii), (Iwxiv), (Iwxv), (Iwxvi),(Iwxvii), (Iwxviii), (Iwxix) or (Iwxx)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹ and R¹⁹ are definedas in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iwxiii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iwxiv), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iwxv),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iwxvi), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iwxvii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iwxviii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iwvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iwxix), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iwxx), preferably in form of the(S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R⁷, R¹⁹ and R²⁵ are defined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4 to            10-membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano,            hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and            C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl,                4 to 10-membered heterocyclyl or C₁₋₆-alkoxy is                optionally substituted with one or more substituent(s)                independently selected from the group consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5 to 10-membered                    heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                    oxo, NR^(8′)R^(9′), C(═OR^(10′) and                    C(═O)NR^(11′)R^(12′),    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl and 5 to 10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5 to            10-membered heterocyclyl or 5 to 10-membered heteroaryl or            the heterocyclic ring formed by R⁸ and R⁹ together with the            N atom to which they are attached is optionally substituted            with one or more substituent(s) independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,                NR^(8″)R^(9″), C(═O)OR^(10″) and C(═O)NR^(11″)R^(12″);    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered            heterocyclyl, C₁₋₃-alkoxy, hydroxy, NR⁸R⁹, SR¹⁰, SOR¹⁰ and            SO₂R¹⁰,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4 to 10-membered                heterocyclyl or C₁₋₃-alkoxy is optionally substituted                with one or more substituent(s) independently selected                from the group consisting of                -   C₁₋₃-alkyl, 5 to 10-membered heterocyclyl,                    C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                    NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR¹¹R¹²    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl and 5 to            10-membered heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3        further ring atoms are selected from N, S and O;        -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl or 5 to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R^(9″);    -   R¹⁰ is independently selected from hydrogen or C₁₋₃-alkyl,        preferably from hydrogen, methyl or ethyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen or C₁₋₃-alkyl, preferably from hydrogen,        methyl or ethyl,    -   R^(8″) and R^(9″) are independently selected from hydrogen or        C₁₋₃-alkyl, preferably from hydrogen, methyl or ethyl,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R⁷ is independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

Suitably R⁷ is independently selected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl and        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl, and        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ixi), (Ixii), (Ixiii), (Ixiv),(Ixv), (Ixvi), (Ixvii) or (Ixviii),

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein R¹, R¹³, R¹⁴, A1, A2,A3, and A4 are defined as in any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Ixi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ixii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ixiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ixiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Ixv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Ixvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Ixvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Ixviii), preferably in form of the (S)-enantiomer.

The invention provides a compound according to the invention and/orembodiments thereof, wherein R¹, R¹⁴, A1, A2, A3, A4, R¹⁹ and R²⁵ aredefined as below.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′);    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,                -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                    substituted with one or more substituents                    independently selected from the group consisting of                    halogen, cyano, hydroxy, preferably each C₁₋₆-alkyl,                    C₁₋₆-alkoxy, is optionally substituted with one or                    more halogen,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH— or —O—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iyi), (Iyii), (Iyiii), (Iyiv),(Iyv), (Iyvi), (Iyvii), (Iyviii), (Iyix), (Iyx), (Iyxi) or (Iyxii)

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein Rand R⁷ are defined asin any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iyi), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iyii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iyiii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iyiv), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iyv), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iyvi), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iyvii),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iyviii), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iyix), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iyx), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iyxi),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iyxii), preferably in form of the (S)-enantiomer.

Optionally, in an embodiment of the invention and/or embodimentsthereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   and    -   R¹⁹ is independently selected from the group consisting of        -   C₆₋₁₀-aryl and 5 to 10-membered heteroaryl,            -   wherein each C₆₋₁₀-aryl or 5 to 10-membered heteroaryl                is optionally substituted with one or more                substituent(s) independently selected from the group                consisting of                -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                    10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to                    10-membered heteroaryl, halogen, cyano, nitro,                    hydroxy, NR²⁰R²¹, C(═O)OR²² and C(═O)NR²³R²⁴,    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, 5 to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5 to 10-membered                heteroaryl, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   and    -   R²⁵ is hydrogen or methyl.

In one embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, C₁₋₃        alkyl or C₁₋₃ alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is a 5 to 10-membered heteroaryl        -   wherein the 5 to 10-membered heteroaryl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,            -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                substituted with one or more substituents independently                selected from the group consisting of halogen, cyano,                hydroxy, preferably each C₁₋₆-alkyl, C₁₋₆-alkoxy, is                optionally substituted with one or more halogen,    -   and    -   R²⁵ is hydrogen or methyl.

In an embodiment of the invention and/or embodiments thereof,

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen or C₁₋₃        alkoxy,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen or C₁₋₃        alkoxy,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen or C₁₋₃        alkoxy,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen or C₁₋₃        alkoxy,    -   wherein none, one or two of A1, A2, A3 and A4 are N,    -   and    -   R¹⁹ is independently selected from 3,5-dichlorophenyl,        2,3-dichlorophenyl, 2,3,5-trifluorophenyl,        3-trifluoromethylphenyl, 3-methoxyphenyl, 2,3-dimethylphenyl,        3-chlorophenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminophenyl,        3,5-difluorophenyl, 2,3-difluorophenyl, 3,4,5-trifluorophenyl,        2-fluoro-3-chlorophenyl, 2-fluoro-5-trifluoromethylphenyl,        naphth-1-yl, 2-fluoro-5-chlorophenyl,        3-fluoro-5-trifluoromethylphenyl, and 2,3,5-trichlorophenyl,        preferably 3-flurorophenyl, 3-chlorophenyl, 2,3-diflurorophenyl        3,5-difluorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl,        2-chloro-3-fluorophenyl, 3-chloro-2-fluorophenyl,        5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl,        5-chloro-2-fluorophenyl, 3,4,5-trifluorophenyl,        2,3,5-trifluorophenyl, 3,5-dichloro-4-fluorphenyl and        3,4,5-trichlorophenyl, more preferably 3-chlorophenyl,        2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,        2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl,        3-chloro-2-fluorophenyl, 5-chloro-3-fluorophenyl,        5-chloro-3-fluorophenyl, 3,5-dichloro-4-fluorophenyl, in        particular 2,3,5-trifluorophenyl, 2,3-dichlorophenyl and        3,5-dichlorophenyl,    -   and    -   R²⁵ is hydrogen or methyl, more preferably hydrogen.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iyxiii), (Iyxiv), (Iyxv), (Iyxvi),(Iyxvii), (Iyxviii), (Iyxix) or (Iyxx))

or a stereoisomer, physiologically acceptable salt, ester, solvate,polymorph, prodrug and mixtures thereof, wherein Rand R⁷ are defined asin any of the embodiments described herein.

In an embodiment of the invention and/or embodiments thereof, thecompounds are according to Formula (Iyxiii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iyxiv), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iyxv),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iyxvi), preferably in form of the (S)-enantiomer. In anembodiment of the invention and/or embodiments thereof, the compoundsare according to Formula (Iyxvii), preferably in form of the(S)-enantiomer. In an embodiment of the invention and/or embodimentsthereof, the compounds are according to Formula (Iyxviii), preferably inform of the (S)-enantiomer. In an embodiment of the invention and/orembodiments thereof, the compounds are according to Formula (Iyxix),preferably in form of the (S)-enantiomer. In an embodiment of theinvention and/or embodiments thereof, the compounds are according toFormula (Iyxx), preferably in form of the (S)-enantiomer.

The compound according to invention can be considered as an “active”agent, which in this context is regarded as a substance that willinhibit the growth of helminths such as Dirofilaria, in particularDirofilaria immitis. The term “inhibiting the growth” indicates that therate of increase in the numbers of a population of a helminth isreduced. Thus, the term includes situations in which the helminthpopulation increases but at a reduced rate, as well as situations wherethe growth of the population is stopped, as well as situations where thenumbers of the helminth in the population are reduced or the populationis even eliminated.

Further, the present invention provides a process for preparing thecompound according to Formula (I) comprising the step of

-   -   reacting a compound of Formula (A)

-   -   with a compound of Formula (B)

-   -   wherein    -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR²R³, COOH, C(═O)OR⁴, SR⁴, SOR⁴, SO₂R⁴, SO₂NR⁵R⁶            and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, NR^(2′)R^(3′),                    C(═O)OR^(4′), SR^(4′), SOR^(4′), SO₂R^(4′),                    SO₂NR^(5′)R^(6′) and C(═O)NR^(5′)R^(6′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R² and R³            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(2″)R^(3″), C(═O)OR^(4″), SR⁴″, SOR⁴, SO₂R^(4″),                SO₂NR^(5″)R^(6″) and C(═O)NR^(5″)R⁶″,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(2′), R^(3′), R^(4′), R^(5′) and R^(6′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(2″), R^(3″), R^(4″), R^(5″) and R^(6″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR⁸R⁹, COOH, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰,            SO₂NR¹¹R¹² and C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, oxo, NR⁸R^(9′),                    C(═O)OR^(10′), SR^(10′), SOR^(10′), SO₂R^(10′),                    SO₂NR^(11′)R^(12′) and C(═O)NR¹¹R¹²,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl, C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(8″)R^(9″), C(═O)OR^(10″), SR^(10″), SOR¹⁰—, SO₂R¹⁰—,                SO₂NR^(11″)R^(12″) and C(═O)NR^(11″)R^(12″),    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R¹³ is hydrogen or C₁₋₃ alkyl,    -   R¹⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, NR^(14′)R^(14″),        wherein R^(14′) and R^(14″) are independently C₁₋₃-alkyl or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or 1R¹³ and R¹⁴ together with the atoms to which        they are attached form a 5 or 6-carbon atoms containing        unsaturated ring, wherein the unsaturated ring is optionally        substituted with one or more C₁₋₃-alkyl, and/or wherein one or        more of the ring-forming carbon atoms are optionally replaced by        —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   R¹⁹ is independently selected from the group consisting of        C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5- to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered                heteroaryl, C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen,                cyano, nitro, hydroxy, mercapto, NR²⁰R²¹, C(═O)OR²²,                SR²², SOR²², SO₂R²², SO₂NR²³R²⁴ and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to            10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁-C₆-alkyl            substituted with C₆₋₁₀-aryl, C₁₋₆-alkyl substituted with 5-            to 10-membered heteroaryl, or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5-            to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered            heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto or the            heterocyclic ring formed by R²⁰ and R²¹ together with the N            atom to which they are attached is optionally substituted            with one or more substituents independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(20′)R^(21′), C(═O)OR^(22′) SR^(22′), SOR^(22′),                SO₂R^(22′), SO₂NR^(23′)R^(24′), and                C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R²⁵ is independently selected from hydrogen and C₁₋₆-alkyl,    -   to obtain the compound according to Formula (I).

In an embodiment of the invention and/or embodiments thereof, as far asR¹, R⁷, R¹³, R¹⁴, A1, A2, A3, A4, R¹⁹ and R²⁵ are concerned, the sameapplies as described above with regard to the compound according to theinvention.

The compounds of Formula (A) and Formula (B) are either commercially orsynthetically available.

In an embodiment of the invention and/or embodiments thereof, thecarboxylic acid of Formula (A) and the amine according to Formula (B)can be submitted to form the corresponding amide group in an organicsolvent in the presence of a coupling agent.

A coupling agent can be regarded as a substance generally facilitatingthe formation of an ester or an amide. The coupling agent reacts with acarboxy group by forming a reactive intermediate which is subsequentlyfurther reacted with an alcohol or an amine to form the final product,i.e. an ester or an amide.

Examples of coupling agents include, but are not limited to,carbodiimides such as N,N′-dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDCxHCl) andN-Cyclohexyl-N′-(2-morpholinoethyl)carbodiimid-methyl-p-toluolsulfonat(CMC), Phosphonium salts such asBenzotriazol-1-yl-oxytripyrrolidino-phosphoniumhexafluorophosphat(PyBOP), aminium salts such as3-[bis(dimethyl-amino)methyliumyl]-3H-benzotriazol-1-oxid-hexafluorphosphat(HBTU) and carbonyldiimidazole (CDI).

In an embodiment of the invention and/or embodiments thereof, thecoupling agent is selected from N,N′-dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDCxHCl) and carbonyldiimidazole (CDI). More preferablythe coupling agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride.

Organic solvents are known to the skilled person.

A suitable organic solvent for the process according to the presentinvention can for example be acetonitrile, dioxane, tetrahydrofuran(THF) and dimethylformamide (DMF), dimethyl sulfoxide (DMSO), preferablydimethylformamide (DMF).

In an embodiment of the invention and/or embodiments thereof, theprocess can be carried out in the presence of an auxiliary alkalinecompound. Suitable alkaline compounds include, but are not limited to,pyridines such as 4-(dimethylamino) pyridine (DMAP), amidines such1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and amines such astriethylamine and diisopropylethylamine (DIPEA), preferably4-(dimethylamino) pyridine (DMAP).

In an embodiment of the invention and/or embodiments thereof, theprocess can be carried out at a temperature of 5° to 120° C., preferablyat 20 to 100° C.

In an alternative embodiment of the invention and/or embodimentsthereof, the carboxylic acid according to Formula (A) can be reactedwith thionyl chloride or oxalyl chloride, preferably oxalyl chloride, toform the corresponding acid chloride. Subsequently the correspondingacid chloride can be submitted to a reaction with the amine according toFormula (B) to obtain the compound of Formula (I).

In an alternative embodiment of the invention and/or embodimentsthereof, the alternative process can be carried out in an organicsolvent and/or in the presence of an auxiliary alkaline compound.

A suitable organic solvent can for example be acetonitrile, toluene,dioxane, tetrahydrofuran, chloroform or dichloromethane.

As far as the auxiliary alkaline compound is concerned, the same appliesas described above, preferred are pyridine, DMAP, triethylamine anddiisopropylethylamine.

Further, the invention provides a veterinary composition comprising thecompound according to the invention and one or more physiologicallyacceptable excipient(s).

Veterinary compositions of the present invention and/or embodimentsthereof comprise a therapeutically effective amount of a compound of thepresent invention and/or embodiments thereof formulated together withone or more physiologically acceptable excipient(s).

Physiologically acceptable excipients are known in the art. For example,they are described in “Gennaro, Remington: The Science and Practice ofPharmacy” (20^(th) Edition, 2000). All such physiologically acceptableexcipients must be substantially pharmaceutically or veterinary pure andnon-toxic in the amounts employed and must be compatible with the activeingredients.

In one preferred embodiment of the invention and/or embodiments thereofthe one or more physiologically acceptable excipient(s) is selected fromcarriers, binders, antioxidants, buffers, sugar components, surfactants,lubricants, stabilizers, flow agents, disintegration agents andpreservatives and mixtures thereof.

As used herein, the term “carrier” means a non-toxic, inert, solid,semi-solid or liquid filler or diluent carrying/encapsulating materialof any type. Some examples of materials that can serve asphysiologically acceptable carriers are, but are not limited to, sugarssuch as lactose, glucose and sucrose; starches such as corn starch andpotato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatine; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; esters such asethyl oleate and ethyl laurate; agar.

A binder is a substance which is capable of making other substancesstick together. The binder is a component that, in case binder is apolymer, preferably has a melting temperature or a glass transitiontemperature (T_(g)) in the range of 25 to 100° C., preferably 35 to 85°C., in particular 40 to 70° C. The glass transition temperature is thetemperature at which a polymer becomes brittle as it cools down and softas it heats up. This means that hydrophilic polymers become soft attemperatures above the glass transition temperature (T_(g)) and becomeplastically deformable without breaking. The glass transitiontemperature or melting point are determined via methods known by theskilled person.

In one preferred embodiment of the invention and/or embodiments thereofthe binder is selected from polyethylene glycol, polypropylene glycol,polyethylene glycol-polypropylene glycol copolymer, microcrystallinewax, glycerol monostearate, hydrogenated castor oil, polyethylene glycolglycerol hydroxystearate, polysaccharides, polyvinylpyrrolidone,polyvinyl alcohol, poly(meth)acrylates, polyvinylpyrrolidone-polyacetatecopolymer and mixtures thereof.

Antioxidants are substances that are used to inhibit oxidation.Antioxidants suitable to be comprised in the present soft chewableveterinary dosage form include, but are not limited to, ascorbic acid,glutathione, tocopherol and its esters, tert-butylhydroquinone (TBHQ),butyl hydroxy anisole (BHA also referred to as 2-tert-butyl-4-hydroxyanisole, 3-tert-butyl-4-hydroxy anisole or a mixture thereof) and butylhydroxy toluene (BHT also referred as 2,6-di tert-butyl 4-methylphenol). It is preferred that the antioxidant is present in theconglomerate. In one preferred embodiment of the invention and/orembodiments thereof antioxidants comprised in the veterinary dosage formmay be in the range of 0.001 to 1.00 weight %.

Buffers are substances to maintain/adjust the pH value of a product.Non-limiting examples of buffers are hydrogen carbonate salts,dihydrogen phosphate salts, hydrogen phosphate salts.

Sugar components are used to sweeten the taste of a product. Theycomprise natural sugars (carbohydrates) as well as sugar substitutes. Inone preferred embodiment of the invention and/or embodiments thereofbuffers comprised in the veterinary dosage form may be in the range of 1to 10 weight %.

Surfactants can be regarded as substances lowering the interfacialtension between two phases. Common surfactants are alkylsulfates (forexample sodium lauryl sulfate), alkyl trimethyl ammonium salts, alcoholethoxylates and the like. In one preferred embodiment of the inventionand/or embodiments thereof surfactants comprised in the veterinarydosage form may be in the range of 0.1 to 10.0 weight %.

Lubricants generally can be regarded as substances which are suitable toreduce friction, such as static friction, sliding friction and rollingfriction. The lubricant is preferably a stearate or fatty acid, morepreferably an earth alkali metal stearate, such as magnesium stearate.In one preferred embodiment of the invention and/or embodiments thereoflubricants comprised in the veterinary dosage form may be in the rangeof 0.1 to 10.0 weight %.

A stabiliser is a physiologically acceptable excipient which helps topreserve the product. Examples include, but are not limited to,alginates, carrageen, gelatine, pectin and natural gums. In onepreferred embodiment of the invention and/or embodiments thereofsurfactants comprised in the veterinary dosage form may be in the rangeof 0.01 to 3.0 weight %.

Flow agents, also referred to as glidants, can be used to improve theflowability. Traditionally, talc was used as glidant but is nowadaysnearly fully replaced by colloidal silica. In one preferred embodimentof the invention and/or embodiments thereof flow agents comprised in theveterinary dosage form may be in the range of 1 to 3 weight %.

Disintegration agents, also referred to as disintegrants, are compoundswhich enhance the ability of the dosage form, preferably the ability ofthe tablet, when in contact with a liquid, preferably water, to breakinto smaller fragments. Non-limiting examples of disintegration agentsinclude sodium carboxymethyl starch, sodium starch glycolate,cross-linked polyvinyl pyrrolidone, sodium carboxymethyl glycolate,preferably sodium starch glycolate. In one preferred embodiment of theinvention and/or embodiments thereof surfactants comprised in theveterinary dosage form may be in the range of 1.0 to 7.0 weight %.

Preservatives are substances that can be added to prevent decompositionby microbial growth or by undesirable chemical changes. Non-limitingexamples include lactic acid, benzoic acid benzoates andhydroxybenzoates. In one preferred embodiment of the invention and/orembodiments thereof surfactants comprised in the veterinary dosage formmay be in the range of 0.01 to 1.0 weight %.

The compounds according to this invention may be administered in variousdosage forms. The term “dosage form” means that the compounds accordingto this invention are formulated into a product suitable foradministering to the animal via the envisaged dosage route. Such dosageforms are sometimes referred to herein as formulations or pharmaceuticalcompositions.

The pharmaceutical compositions of this invention and/or embodimentsthereof can be administered to animals orally, rectally, intravaginally,parenterally, topically, buccally or nasally.

In one preferred embodiment of the invention and/or embodiments thereofdosage forms useful for oral administration can be liquid or soliddosage forms.

Liquid dosage forms of the compounds are generally solutions,suspensions or emulsions. A solution is a mixture of two or morecomponents that form a single phase that is homogeneous down to themolecular level. A suspension consists of insoluble solid particlesdispersed in a liquid medium, with the solid particles accounting forabout 0.5% to about 30% of the suspension. The liquid may be aqueous,oily or both. An emulsion is a heterogeneous dispersion of oneimmiscible liquid in another; it relies on an emulsifying agent forstability. A dry powder (or granule) for reconstitution is mixed andreconstituted with a diluent (e.g. water) as a solution, or as asuspension immediately prior to dosing such as by injection. Theprincipal advantage of this dosage form is that it overcomes the problemof instability in solution or suspension.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, micro-emulsions, solutions, suspensions, syrups,drenches in feed or drinking water formulations and elixirs. A drench isa liquid oral formulation that is administered directly into themouth/throat of an animal, especially a dog, by means of a “drench gun”or syringe or another suitable device. When the composition isadministered in the animal recipient's drinking water or as a drench, itmay be convenient to use a solution or suspension formulation. Thisformulation can, for example, be a concentrated suspension that is mixedwith water or a dry preparation that is mixed and suspended in thewater. In addition to the active compounds, the liquid dosage forms maycontain inert diluents commonly used in the art such as, for example,water or other solvents, solubilizing agents and emulsifiers such asethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils (in particular cottonseed, groundnut, corn,germ, olive castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitane andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavouring and perfuming agents.

Solid dosage forms for oral administration include capsules, tablets,dragées, pills, powders and granules, chewable treats, premixes andmedicated blocks. In such solid dosage forms, the active compound ismixed with at least one inert, pharmaceutically acceptable excipient orcarrier such as sodium citrate or dicalcium phosphate and/or a) fillersor extenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid; b) binders such as, for example, carboxymethyl-cellulose,alginates, gelatine, polyvinyl pyrrolidinone, sucrose and acacia; c)humectants such as glycerol; d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates and sodium carbonate; e) solution retarding agents such asparaffin; f) absorption accelerators such as quaternary ammoniumcompounds; g) wetting agents such as, for example, acetyl alcohol andglycerol monostearate; h) absorbents such as kaolin and bentonite clayand i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragées, capsules, pills and granules can be prepared with coatings andshells such as enteric coatings and other coatings well known in thepharmaceutical formulating art such as enteric coatings,release-controlling coatings and other well-known coatings. In suchsolid dosage forms the active compound may be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms mayalso comprise, as is normal practice, additional substances other thaninert diluents, e.g. tableting lubricants and other tableting aids sucha magnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally in a delayed manner. Examples of such embedding compositionsinclude polymeric substances and waxes.

Solid compositions of a similar type may also be employed as fillers insoft and hard gelatine capsules using such excipients as lactose as wellas high molecular weight polyethylene glycols and the like.

Solid oral formulations are either administered directly to an animal(tablet, capsule) or mixed with the feed or via medicated feed blocks.

When the oral formulation is administered via a non-human animal's feed,it may for example be fed as a discrete feed or as a chewable treat.Alternatively (or additionally), it may for example be intimatelydispersed in the animal recipient's regular feed, used as a top dressingor in the form of solid pellets, paste or liquid that is added to thefinished feed. When the oral formulation is administered as a feedadditive, it may be convenient to prepare a “premix” in which the oralformulation is dispersed in a small amount of a liquid or solid carrier.This “premix” is, in turn, dispersed in the animal's regular feed usingfor example a conventional mixer.

In one preferred embodiment of the invention and/or embodiments thereofdosage forms useful for rectal and vaginal administration can beregarded as semi solid dosage forms.

Compositions for rectal or vaginal administration can be prepared bymixing the compounds of this invention with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum or vaginal cavity andrelease the active compound.

In one preferred embodiment of the invention and/or embodiments thereofthe dosage forms are useful for parenteral administrations. One dosageroute (administration route) is the parenteral, especially injectionadministration (e.g. subcutaneous injection, intravenous injection,intramuscular injection etc.). Parenteral formulations and deliverysystems for non-oral routes comprise liquids (e.g. solutions,suspensions, emulsions and dry powders for reconstitution), semi-solidsand solids (e.g. implants). The majority of implants that are used inveterinary medicine are compressed tablets or dispersed matrix systemsin which the drug is uniformly dispersed within a nondegradable polymeror alternatively extrusion products. In one embodiment the compounds ofthe current invention are administered subcutaneously.

Injectable formulations, for example sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil can beemployed, including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example by filtrationthrough a bacterial-retaining filter or by incorporating sterilizingagents in the form of sterile solid compositions that can be dissolvedor dispersed in sterile water or other sterile injectable media prior touse.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends on its rate of dissolution that,in turn, may depend on crystal size and crystalline form. Alternatively,delayed absorption of a parenterally administered drug form may beaccomplished by dissolving or suspending the drug in an oil vehicle.Injectable depot forms are made by forming microencapsulation matricesof the drug in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations may also be prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues.

In one preferred embodiment of the invention and/or embodiments thereofdosage forms useful for topical administration (also referred to astransdermal administration) of a compound of this invention includeointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or patches. The active component is admixed under sterileconditions with a pharmaceutically acceptable carrier and any neededpreservatives or buffers as may be required. Ophthalmic formulations,ear drops and the like are also contemplated as being within the scopeof this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide or mixtures thereof.

Compounds of the invention may also be formulated for use as topicalpowders and sprays that can contain, in addition to the compounds ofthis invention, excipients such as lactose, talc, silicic acid,aluminium hydroxide, calcium silicates and polyamide powder or mixturesof these substances.

Sprays can additionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin.

The rate can be controlled by either providing a rate controllingmembrane or by dispersing the compound in a polymer matrix or gel.

In one preferred embodiment of the invention and/or embodiments thereofdosage forms useful for buccal administration of a compound of thisinvention include orally disintegrating tablets (ODT), films, sublingualdrops, lozenges, effervescent buccal tablets, toothpaste and mouthwash.

In one preferred embodiment of the invention and/or embodiments thereofdosage forms useful for nasal administration of a compound of thisinvention include liquid aerosols or inhalable dry powders. Liquidaerosol formulations may be nebulized predominantly into particle sizesthat can be delivered to the terminal and respiratory bronchioles.

Liquid aerosol and inhalable dry powder formulations are preferablydelivered throughout the endobronchial tree to the terminal bronchiolesand eventually to the parenchymal tissue.

Aerosolized formulations of the invention may be delivered using anaerosol-forming device, such as a jet, vibrating porous plate orultrasonic nebulizer, preferably selected to allow the formation ofaerosol particles having a mass medium average diameter predominantlybetween 1 to 5 pm.

Further, the formulation preferably has a balanced osmolarity ionicstrength and chloride concentration and the smallest aerosolizablevolume able to deliver an effective dose of the compounds of theinvention to the site of the infection. Additionally, the aerosolizedFormulation preferably does not impair negatively the functionality ofthe airways and does not cause undesirable side effects.

Aerosolization devices suitable for the administration of aerosolformulations of the invention include for example jet, vibrating porousplate, ultrasonic nebulizers and energized dry powder inhalers that areable to nebulize the formulation of the invention into aerosol particlespredominantly in the size range of 1-5 pm. Predominantly in thisapplication means that at least 70% but preferably more than 90% of allgenerated aerosol particles are in the 1 to 5 pm range. A jet nebulizerworks by air pressure to break a liquid solution into aerosol droplets.Vibrating porous plate nebulizers work by using a sonic vacuum producedby a rapidly vibrating porous plate to extrude a solvent droplet througha porous plate. An ultrasonic nebulizer works by a piezoelectric crystalthat shears a liquid into small aerosol droplets.

The concentration of the compounds according to this invention in theapplied dosage form may vary widely depending on for example the dosageroute. In general, the concentration of the present compound orembodiments thereof in the formulation according to the presentinvention or embodiments thereof is from 1 to 70% by weight, based onthe total weight of the formulation. In some embodiments theconcentration is from 1 to 50% by weight or from 10 to 50% by weight. Inother embodiments, the concentration is from 35 to 65% by weight, from40 to 60% by weight, from 45 to 55% by weight or about 50% by weight.

Preferred concentrations of the compound according to the presentinvention or embodiments thereof dissolved in drinking water are from0.01 to 0.05% weight by volume, particularly 0.01 to 0.025%, and in-feedfrom 100 to 400 ppm (g/metric ton), particularly 100 to 200 ppm.

In a preferred embodiment of the invention or embodiments thereof theveterinary compositions of the present invention and/or embodimentsthereof comprise a therapeutically effective amount of a compound of thepresent invention and/or embodiments thereof as the single active agent.

In a preferred embodiment of the invention or embodiments thereof theveterinary compositions of the present invention and/or embodimentsthereof comprise a therapeutically effective amount of a compound of thepresent invention and/or embodiments thereof in combination with one ormore other known active agent(s). These one or more other known activeagent(s) may be of a similar spectrum as the present compound tosynergistically enhance treatment of the infections covered by thespectrum of the present compound. Alternatively, these one or more otherknown active agent(s) may be of a different spectrum as the presentcompound, when multiple parasitic organisms are suspected in whichanother agent of a different spectrum may be required in addition to thepresent compound. The treatment can involve administering a compositionhaving the present compound and one or more further known activeagent(s) or administration of the inventive compounds followed by orpreceded by administration of one or more additional active agent(s).

Particular combinations comprise a) one or more compounds according tothis invention with b) one or more pharmaceutically acceptable activecompounds which differ in structure from component a). The activecompounds b) are preferably anthelmintic compounds, more preferablyselected from the group consisting of avermectins (e.g., ivermectin,selamectin, doramectin, abamectin, emamectin and eprinomectin);milbemycins (moxidectin and milbemycin oxime); pro-benzimidazoles (e.g.,febantel, netobimin, and thiophanate); benzimidazole derivatives, suchas a thiazole benzimidazole derivative (e.g., thiabendazole andcambendazole) or a carbamate benzimidazole derivatives (e.g.,fenbendazole, albendazole (oxide), mebendazole, oxfendazole,parbendazole, oxibendazole, flubendazole, and triclabendazole); animidazothiazole (e.g., levamisole and tetramisole); atetrahydropyrimidine (morantel and pyrantel), organophosphates (e.g.,trichlorphon, haloxon, dichlorvos, and naphthalophos); salicylanilides(e.g., closantel, oxyclozanide, rafoxanide, and niclosamide);nitrophenolic compounds (e.g., nitroxynil and nitroscanate);benzenedisulphonamides (e.g., clorsulon); pyrazineisoquinolines (e.g.,praziquantel and epsiprantel); heterocyclic compounds (e.g., piperazine,diethylcarbamazine, dichlorophen, and phenothiazine); arsenicals (e.g.,thiacetarsamide, melorsamine, and arsenamide); cyclooctadepsipeptides(e.g., emodepside, PF1022A); paraherquamides (e.g., derquantel,paraherquanide); and amino-acetonitrile compounds (e.g. monepantel, AAD1566); tribendimidine (amidine compound); amidine compounds (e.g.,amidantel and tribendimidin), including all pharmaceutically acceptableforms, such as salts, solvates or N-oxides.

The compounds as described in this specification can be combined withpharmaceutically acceptable insecticides or acaricides. Suchpharmaceutically acceptable insecticides and acaricides include, forexample, acetamiprid, acetoprole, amitraz, amidoflumet, avermectin,azadirachtin, bifenthrin, bifenazate, broflanilide, buprofezin,bistrifluron, chlorfenapyr, chlorfluazuron, chlorantraniliprole,chlorpyrifos, chromafenozide, clothianidin, cyantraniliprole,cyflumetofen, 13-cyfluthrin, cyhalothrin, Acyhalothrin, cymiazolecypermethrin, cyromazine, deltamethrin, demiditraz, diafenthiuron,diazinon, diflubenzuron, dimefluthrin, dinotefuran, emamectin,esfenvalerate, ethiprole, fenoxycarb, fenpropathrin, fenvalerate,fipronil, flonicamid, flubendiamide, flucythrinate, tau-fluvalinate,flufenoxuron, halofenozide, hexaflumuron, imidacloprid, indoxacarb,lufenuron, metaflumizone, methoprene, metofluthrin, methoxyfenozide,nitenpyram, novaluron, noviflumuron, permethrin, phosmet, profluthrin,protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridalyl,pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine,sisapronil, spinetoram, spinosad, spirodiclofen, spiromesifen,spirotetramat, sulfoxaflor, tebufenozide, tebufenpyrad, teflubenzuron,tefluthrin, tetrachlorvinphos, tetramethylfluthrin, thiacloprid,thiamethoxam, tigolaner, tolfenpyrad, tralomethrin, and triflumuron.General references discussing antiparasitic agents, such as insecticidesand acaricides, include, for example, The Pesticide Manual, 18thEdition, J. A. Turner, Ed., British Crop Protection CouncilPublications, U.K. (2018).

The compounds as described in this specification can be combined withpharmaceutically acceptable insect growth regulators. Suchpharmaceutically acceptable insect growth regulators include, forexample, methoprene, pyriproxyfen, tetrahydroazadirachtin,chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron,flufenoxuron, hexaflumuron, lufenuron, ifenuron, tebufenozide, andtriflumuron. These compounds tend to provide both initial and sustainedtreatment of parasite infections at all stages of insect development,including eggs, on the animal subject, as well as within the environmentof the animal subject.

The compounds as described in this specification can be combined withpharmaceutically acceptable anti-protozoals. Such pharmaceuticallyacceptable anti-protozoals include, for example, triazintriones like,for example, toltrazuril and ponazuril and triazindiones such asclazuril, diclazuril and letrazuril. In some contemplated embodiments,the compounds are administered with dihydroazole compounds, such as, forexample, compounds discussed in WO 2010/75591.

In some contemplated embodiments, the compounds of the present inventionare administered with anthelminic proteins, such as, for exampleBacillus thuringensiscrystal proteins e.g. described in WO 2010/053517.

In some contemplated embodiments, the compounds are administered withpyridylmethylamine derivatives, such as, for example, pyridylmethylaminederivatives discussed in EP0539588 WO2007/115643.

In some contemplated embodiments, the compounds is administered withnodulisporic acids and derivatives thereof, such as, for example,compounds discussed in U.S. Pat. Nos. 5,399,582; 5,945,317; 5,962,499;5,834,260; 6,221,894; or U.S. Pat. No. 5,595,991; or WO1996/29073.

In some contemplated embodiments, the compounds are administered withisoxazoline compounds (e.g., sarolaner, fluralaner, lotilaner,afoxolaner, fluxametamide, isocycloseram) Other antiparasitic compoundscontemplated to be useful in combination therapies with the compoundsinclude, for example, imidazo[1,2-b] pyridazine compounds discussed inUS2005-0182059; 1-(4-Mono anddihalomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compoundsdiscussed U.S. Pat. No. 7,361,689; trifluoromethanesulfonanilide oximeether compounds discussed in U.S. Pat. No. 7,312,248;n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide andn-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamide compoundsdiscussed in US2006-0281695; and2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile compounds discussed inUS2006/0128779; azole compounds discussed in WO2017/192385,WO2019/170626, WO2019/197468, WO2019/201835, WO2019/206799,WO2019/215198, WO2020/053364, WO2020/053365, WO2020/070049,WO2020/079198, WO2020/094363, WO2020/169445, WO2020/193341,WO2020/201079, WO2020/201398, WO2020/208036, WO2020/212235, andWO2020/219871.

Further aspects regarding the formulation of drugs and variousexcipients are found for example in Gennaro, A. R., et al., eds.,Remington: The Science and Practice of Pharmacy (Lippincott Williams &Wilkins, 20^(th) Ed., 2000). Moreover, methods of formulation are wellknown in the art and are disclosed for example in Remington: The Scienceand Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19^(th)Edition (1995).

As indicated above, the compound according to the invention can beconsidered as an “active” agent, which is regarded as a substance thatwill inhibit the growth of helminths such as Dirofilaria, in particularDirofilaria immitis. The term “inhibiting the growth” indicates that therate of increase in the numbers of a population of a helminth isreduced.

It is understood that the term “treating” or “treatment” used hereinincludes prophylactic, metaphylactic and therapeutic or curativetreatment. Prophylactic or metaphylactic treatment, i.e. deworming, iscommonly used to prevent helminth infection so to control parasiticinfections in animals. In addition, helminths can infect humans andtherefore pose a threat to human health as well. Prophylactic treatmentscomprise treatments which are done at regular intervals such as 1-6times per year, or 2-4 times per year or 1-4 per month, or evencontinuous such as via the drinking water. Metaphylactic treatmentcomprise treatment of all animal e.g. in the same area, when a number ofanimals is diagnosed to prevent the spread of the parasite to the otheranimals. Metaphylactic and prophylactic treatment may also occurseasonal, e.g. when the vector is especially active.

In therapeutic or curative treatment the compounds are administeredafter clinical diagnosis. In this method, there is reduced expenses foranthelmintics, possibility of selection for resistance is significantlyreduced if only some animals are treated and this will ensure thepresence of a susceptible parasite population within the herd or flock,but its disadvantage is that, it requires regular monitoring whichincreases labour input. In a preferred embodiment the compoundsaccording to this invention are used to treat a helminth infection, suchas an infection caused by one or more helminths selected from the groupconsisting of a) cestodes: e.g. Anaplocephala spp.; Dipylidium spp.;Diphyllobothrium spp.; Echinococcus spp.; Moniezia spp.; Taenia spp.; b)trematodes e.g. Dicrocoelium spp.; Fasciola spp.; Paramphistomum spp.;Schistosoma spp.; or c) nematodes, e.g. Acanthocheilonema spp.;Ancylostoma spp.; Anecator spp.; Ascaridia spp.; Ascaris spp.; Brugiaspp.; Bunostomum spp.; Capillaria spp.; Chabertia spp.; Cooperia spp.;Cyathostomum spp.; Cylicocyclus spp.; Cylicodontophorus spp.;Cylicostephanus spp.; Craterostomum spp.; Dictyocaulus spp.;Dipetalonema spp; Dirofilaria spp.; Dracunculus spp.; Enterobius spp.;Filaroides spp.; Habronema spp.; Haemonchus spp.; Heterakis spp.;Hyostrongylus spp.; Metastrongylus spp.; Meullerius spp. Necator spp.;Nematodirus spp.; Nippostrongylus spp.; Oesophagostomum spp.; Onchocercaspp.; Oncocercidae spp; Ostertagia spp.; Oxyuris spp.; Parascaris spp.;Stephanurus spp.; Strongylus spp.; Syngamus spp.; Toxocara spp.;Strongyloides spp.; Teladorsagia spp.; Toxascaris spp.; Trichinellaspp.; Trichuris spp.; Trichostrongylus spp.; Triodontophorous spp.;Uncinaria spp., and/or Wuchereria spp.; preferably nematodes; inparticular Dirofilaria spp.; Haemonchus spp.; Ascaridia spp; Strongylusspp; especially Dirofilaria immitis.

In particular the compounds according to the present invention or theveterinary composition according to present invention are administeredto treat or prevent disorders/diseases caused by one or more helminthsselected from the group consisting a) nematodes: Ostertagia ostertagi,Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Haemonchusplacei, Haemonchus contortus, Nematodirus helvetianus, Nematodirusspathiger, Trichostrongylus colubriformis, Trichostrongyluscircumcincta, Oesophagostomum venulosum, Chabertia ovina, Dictyocaulusviviparous, Dictyocaulus filaria, Dirofilaria immitis, Dirofilariarepens; b) Trematodes: Fasciola hepatica, Fascioloides magna,Dicrocoelium dentriticum, Paramphistomum cervi, c) Cestodes: Moneziaexpansa.

The present invention provides the compounds according to the inventionor the veterinary composition according to the present invention for useas a medicament. In a preferred embodiment the compounds according tothe invention or the veterinary composition according to the presentinvention are suitable for use as a medicament for the treatment ofhelminthiasis and in particular heartworm disease.

The compounds according to the present invention or the veterinarycomposition according to the present invention are used to make amedicament. In a preferred embodiment the compounds according to thepresent invention or the veterinary composition according to the presentinvention are used to make a medicament for the treatment ofhelminthiasis and in particular heartworm disease.

Further, the invention provides the use of the compound according to thepresent invention or the veterinary composition according to the presentinvention for the manufacture of a medicament.

Further, the invention provides the use of the compounds of the presentinvention or the veterinary composition according to the presentinvention for the manufacture of a medicament for the treatment ofhelminthiasis and in particular heartworm disease. Preferably, thecompounds of the present invention or the veterinary compositionaccording to the present invention are used for the manufacture of amedicament for the treatment of helminthiasis and in particularheartworm disease.

Moreover, the present invention provides the compounds according to thepresent invention or the composition of the present invention for use inthe treatment of disorders/diseases caused by helminths, preferably byone or more helminths selected from the group consisting of a) cestodes:e.g. Anaplocephala spp.; Dipylidium spp.; Diphyllobothrium spp.;Echinococcus spp.; Moniezia spp.; Taenia spp.; b) trematodes e.g.Dicrocoelium spp.; Fasciola spp.; Paramphistomum spp.; Schistosoma spp.;or c) nematodes, e.g. Acanthocheilonema spp.; Ancylostoma spp.; Anecatorspp.; Ascaridia spp.; Ascaris spp.; Brugia spp.; Bunostomum spp.;Capillaria spp.; Chabertia spp.; Cooperia spp.; Cyathostomum spp.;Cylicocyclus spp.; Cylicodontophorus spp.; Cylicostephanus spp.;Craterostomum spp.; Dictyocaulus spp.; Dipetalonema spp; Dirofilariaspp.; Dracunculus spp.; Enterobius spp.; Filaroides spp.; Habronemaspp.; Haemonchus spp.; Heterakis spp.; Hyostrongylus spp.;Metastrongylus spp.; Meullerius spp. Necator spp.; Nematodirus spp.;Nippostrongylus spp.; Oesophagostomum spp.; Onchocerca spp.;Oncocercidae spp; Ostertagia spp.; Oxyuris spp.; Parascaris spp.;Stephanurus spp.; Strongylus spp.; Syngamus spp.; Toxocara spp.;Strongyloides spp.; Teladorsagia spp.; Toxascaris spp.; Trichinellaspp.; Trichuris spp.; Trichostrongylus spp.; Triodontophorous spp.;Uncinaria spp., and/or Wuchereria spp.; more preferably nematodes, inparticular Dirofilaria spp.; Haemonchus spp.; Ascaridia spp; Strongylusspp and Oesophagostomun dentatum, especially Dirofilaria immitis.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of filariasis and inparticular heartworm disease. In a preferred embodiment of the inventionor embodiments thereof, the compounds according to the present inventionor the composition of the present invention are for use in the treatmentof disorders/diseases caused by helminths, wherein the helminths areDirofilaria spp., more in particular Dirofilaria repens or Dirofilariaimmitis.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of haemonchosis. In apreferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Haemonchus spp. and inparticular Haemonchus placei and Haemonchus contortus.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of ascaridiasis. In apreferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Ascaridia galli.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of oesophagostomiasis. Ina preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Oesophagostomum spp. andin particular Oesophagostomum venulosum and Oesophagostomum dentatum.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of Trichostrongylusinfection. In a preferred embodiment of the invention or embodimentsthereof, the compounds according to the present invention or thecomposition of the present invention are for use in the treatment ofdisorders/diseases caused by helminths, wherein the helminths areTrichostrongylus spp. and in particular Trichostrongylus axei andTrichostrongylus colubriformis.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of Ostertagiosis. In apreferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Ostertagia spp. and inparticular Ostertagia ostertagi.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of Cooperia infection. Ina preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Cooperia spp. and inparticular Cooperia oncophora.

In a preferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of Nematodiriasis. In apreferred embodiment of the invention or embodiments thereof, thecompounds according to the present invention or the composition of thepresent invention are for use in the treatment of disorders/diseasescaused by helminths, wherein the helminths are Nematodirus spp. and inparticular Nematodirus helvetianus, Nematodirus spathiger.

It is contemplated that the compounds according to this invention andcompounds corresponding to the use according to the invention may beused to treat animals, including humans and non-human animals,especially non-human mammals. Such non-human mammals include, forexample, livestock mammals (e.g., swine, livestock ruminants likebovines, sheep, goats, etc.), laboratory mammals (e.g., mice, rats,jirds, etc.), companion mammals (e.g., dogs, cats, equines, etc.), andwild and zoo mammals (e.g., buffalo, deer, etc.). It is contemplatedthat the compounds also are suitable to treat non-mammals, such aspoultry (e.g., turkeys, chickens, ducks, etc.) and fish (e.g., salmon,trout, koi, etc.).

In the following the use of the compounds as disclosed and covered bythe general structures disclosed in this application for use in thetreatment of heartworm disease, especially if associated withDirofilaria, in particular Dirofilaria immitis, is sometimes referred toas “use according to the invention”.

It has been shown by the inventors that the compounds of the currentinvention as disclosed and defined earlier are especially suitable forthe treatment of heartworm disease, especially in dogs.

The compounds according to the present invention or the veterinarycomposition according to present invention are administered to treat orprevent disorders/diseases caused by one or more helminths selected fromthe group consisting of a) cestodes: e.g. Acanthocheilonema spp.;Anaplocephala spp.; Dipylidium spp.; Diphyllobothrium spp.; Echinococcusspp.; Moniezia spp.; Taenia spp.; b) trematodes e.g. Dicrocoelium spp.;Fasciola spp.; Paramphistomum spp.; Schistosoma spp.; or c) nematodes,e.g. Ancylostoma spp.; Anecator spp.; Ascaridia spp.; Ascaris spp.;Brugia spp.; Bunostomum spp.; Capillaria spp.; Chabertia spp.; Cooperiaspp.; Cyathostomum spp.; Cylicocyclus spp.; Cylicodontophorus spp.;Cylicostephanus spp.; Craterostomum spp.; Dictyocaulus spp.;Dipetalonema spp; Dirofilaria spp.; Dracunculus spp.; Enterobius spp.;Filaroides spp.; Habronema spp.; Haemonchus spp.; Heterakis spp.;Hyostrongylus spp.; Metastrongylus spp.; Meullerius spp. Necator spp.;Nematodirus spp.; Nippostrongylus spp.; Oesophagostomum spp.; Onchocercaspp.; Oncocercidae spp; Ostertagia spp.; Oxyuris spp.; Parascaris spp.;Stephanurus spp.; Strongylus spp.; Syngamus spp.; Toxocara spp.;Strongyloides spp.; Teladorsagia spp.; Toxascaris spp.; Trichinellaspp.; Trichuris spp.; Trichostrongylus spp.; Triodontophorous spp.;Uncinaria spp., and/or Wuchereria spp.; more preferably nematodes, inparticular Dirofilaria spp.; Haemonchus spp.; Ascaridia spp; Strongylusspp and Oesophagostomun dentatum, especially Dirofilaria immitis. Morepreferably, the compounds according to the present invention or theveterinary composition according to present invention are administeredto treat or prevent heartworm disease.

In particular the compounds according to the present invention or theveterinary composition according to present invention are administeredto treat or prevent disorders/diseases caused by one or more helminthsselected from the group consisting a) nematodes: Ostertagia ostertagi,Cooperia oncophora, Cooperia punctata, Trichostrongylus axei, Haemonchusplacei, Haemonchus contortus, Nematodirus helvetianus, Nematodirusspathiger, Trichostrongylus colubriformis, Trichostrongyluscircumcincta, Oesophagostomum venulosum, Chabertia ovina, Dictyocaulusviviparous, Dictyocaulus filaria, Dirofilaria immitis, Dirofilariarepens; b) Trematodes: Fasciola hepatica, Fascioloides magna,Dicrocoelium dentriticum, Paramphistomum cervi, c) Cestodes: Moneziaexpansa.

The term “treatment” as used herein refers to reversing, alleviating,inhibiting the progress of a disease, disorder or condition. In case ofthe heartworm disease, this means that the clinical symptoms (reducedfunction of lung, heart, liver and/or kidney) are alleviated.Prophylactic use is expressly contemplated, especially in the treatmentof heartworm. It is advantageous to prophylactically treat helminthinfection by deworming.

The term “treatment” as used herein also refers to inhibiting thegrowth, migration or survival of larval stages of helminths such asDirofilaria, especially Dirofilaria immitis, after these larval stageshave been transmitted to a mammalian host by the bite of a vector suchas a mosquito.

Thus, the invention provides a method of treating a disease caused byhelminths which comprises administering to an animal, in particular adog, a therapeutically effective amount of a compound according to thepresent invention or the composition according to the present invention.In other words, the invention provides a method of treating filariasisand especially heartworm disease comprising administering atherapeutically effective amount of a compound according to theinvention or the composition according to the present invention to amammal, in particular a dog, in need thereof.

The invention is also directed to a method for treating an animal withdiseases caused by a nematode comprising administering to the subject inneed thereof an effective amount of a compound according to the presentinvention or a composition according to the present invention and/orembodiments thereof, wherein the helminth is a nematode and is at leastone selected from the group of Dirofilaria spp., in particularDirofilaria immitis. Suitably the subject is a mammal, in particular adog or a cat, especially a dog.

The invention is also directed to a method for treating a mammal,preferably a dog, suffering from a disease caused by a helminth, inparticular a nematode, comprising administering to the subject in needthereof an effective amount of a compound according the presentinvention or the composition according to the present invention and/orembodiments thereof, wherein the nematode is at least one selected fromthe group of Dirofilaria, in particular Dirofilaria immitis.

In a preferred embodiment the compounds according to this invention areused to treat a disease caused by nematodes in an animal, wherein thenematode is at least one of helminths such as Dirofilaria, in particularDirofilaria immitis, comprising administering an effective amount of acompound according to the invention to the animal in need thereof.

According to the treatment by the compounds of the present inventionand/or embodiments thereof, diseases caused by helminths, in particularnematodes, especially Dirofilaria, more especially Dirofilaria immitis,are treated or prevented in a mammal, in particular a dog, byadministering to the animal a therapeutically effective amount of acompound of the invention in such amounts and for such time as isnecessary to achieve the desired result.

A “therapeutically effective amount” of a compound of the inventionand/or embodiments thereof means a sufficient amount of the compoundaccording to the present invention or the composition according to thepresent invention for treating heartworm disease, at a reasonablebenefit/risk ratio applicable to any medical treatment. It will beunderstood, however, that the total daily usage of a compound accordingto the invention and a composition according to present invention willbe decided by the attending physician or veterinary doctor within thescope of sound medical judgment. The specific therapeutically effectivedose level for any particular animal will depend on a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of theanimal; the time of administration, route of administration and rate ofexcretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

When the compound according to this invention is administered orally orparenterally by subcutaneous injection, the total dose is preferablygreater than about 0.001 mg/kg (i.e. 0.001 milligram of compoundaccording to this invention per kilogram body weight of the treatedanimal). In some such embodiments, the total dose is from about 0.001 toabout 200 mg/kg, from about 0.01 to about 20 mg/kg, from about 0.1 toabout 10 mg/kg or from about 1 to about 20 mg/kg. The same dose rangemay be suitable for other dosage routes. The desired dose, however, maybe less in some instances where the compound according to this inventionis administered intravenously.

Protection is preferably for at least 7 days, more preferably for atleast 10 days, more preferably for at least 2 weeks, more preferably forat least 3 weeks, more preferably for at least 4 weeks. The protectionis for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20 weeks or more. Preferably the protection is for at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more.

The dose used to control diseases caused by a helminth such asDirofilaria immitis might vary with the compound, the severity of thedisease and the age, weight and condition of the animal, in particularthe dog. The total dose required for several days' protection willgenerally, however, be in the range of from about 0.1 to about 200 mg/kgbodyweight and preferably will be in the range of from about 1 to about100 mg/kg. Preferably protection is for at least seven days, morepreferably at least 2 weeks, more preferably at least 1 month, and evenmore preferably for at least 1, 2, 3, 4, 5, or 6 months.

Protection for up to about seven days can be provided by a single dose;the length of protection will depend on the dose given. The total dosecan also be divided into smaller doses given at intervals, such as oncedaily for two to seven days. Obviously, other suitable dosage regimenscan be constructed.

Especially preferred is the use of the compounds according to thepresent invention or the composition according to the present inventionin dogs. The compounds according to the present invention or thecomposition according to the present invention can be used in animals ofdifferent weights, including animals of a weight higher than 35 kg.

Other exemplary animals that can be treated with the compounds accordingto the present invention or the composition according to the presentinvention are smaller pets such as cats. In one embodiment the compoundsaccording to the present invention or the composition according to thepresent invention are used to treat diseases such as severe lungdisease, heart failure and damage to other inner organs caused byDirofilaria, more especially Dirofilaria immitis.

In one embodiment, the animal that is treated is a dog and the diseasethat is treated is heartworm disease.

In a preferred embodiment of the invention or embodiments thereof asingle administration of a composition according to this invention issufficient to treat or prevent a disease caused by helminth, such as anematode, in particular Dirofilaria immitis, or at least to diminish theclinical symptoms in the diseased animal. This can be called “one shot”administration. Although the administration of such a “one shot” singledose is very suitable, it is contemplated that multiple doses can beused, e.g. two administrations 12-24 hours apart or alternatively twoadministrations 48-72 hours apart.

Factors affecting the preferred dosage may include for example thedisease to be treated, the type (e.g. species and breed), age, size,sex, diet, activity and condition of the of the diseased animal, thedosage route, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound according to the present invention and the compositionadministered and whether the compound according to the present inventionis administered as part of a combination of active ingredients. Thus,the preferred amount of the compound according to this invention canvary and can therefore deviate from the typical dosages set forth above.Determining such dosage adjustments is generally within the skill ofthose in the art. The effective dosage will vary; for example, forprophylactic treatment relatively low doses may be be administered overan extended time or relatively high doses may be administered in asingle treatment. The formulation type selected for a dosage form in anyinstance will depend on the particular purpose envisaged and thephysical, chemical and biological properties of the compound accordingto this invention.

The veterinary compositions, the uses as medicament and uses in thetreatment of diseases caused by helminths, in particular nematodes,especially Dirofilaria immitis, and methods according to the presentinvention encompass methods wherein a compound according to thisinvention is the sole active ingredient administered to the recipientanimal. It is contemplated, however, that the veterinary compositions,the uses as medicament and uses in the treatment of diseases caused bynematodes, in particular Dirofilaria immitis, and methods according tothe present invention also encompass combination therapies wherein acompound is administered in combination with one or more otherpharmaceutically acceptable active ingredient(s). The other activeingredient(s) may be, for example, one or more other compounds accordingto this invention. Alternatively (or additionally), the other activeingredient(s) may be one or more pharmaceutically acceptable compound(s)that are not compounds according to this invention. The other activeingredient(s) may target the same and/or different diseases orconditions.

Contemplated active ingredient(s) that may be administered incombination with the compounds according to the present inventioninclude, for example, antibacterials, anti-inflammatories,pharmaceutically acceptable anthelmintics, insecticides and acaricides,insect growth regulators, hormones, immunostimulants, dermatologicalpreparations (e.g. antiseptics and disinfectants) and immunobiologicals(e.g. vaccines and antisera) for disease prevention.

Particular combinations comprise a) one or more compounds according tothis invention with b) one or more pharmaceutically acceptable activecompounds which differ in structure from component a). The activecompounds b) are preferably anthelmintic compounds, more preferablyselected from the group consisting of avermectins (e.g., ivermectin,selamectin, doramectin, abamectin, emamectin and eprinomectin);milbemycins (moxidectin and milbemycin oxime); pro-benzimidazoles (e.g.,febantel, netobimin, and thiophanate); benzimidazole derivatives, suchas a thiazole benzimidazole derivative (e.g., thiabendazole andcambendazole) or a carbamate benzimidazole derivatives (e.g.,fenbendazole, albendazole (oxide), mebendazole, oxfendazole,parbendazole, oxibendazole, flubendazole, and triclabendazole); animidazothiazole (e.g., levamisole and tetramisole); atetrahydropyrimidine (morantel and pyrantel), organophosphates (e.g.,trichlorphon, haloxon, dichlorvos, and naphthalophos); salicylanilides(e.g., closantel, oxyclozanide, rafoxanide, and niclosamide);nitrophenolic compounds (e.g., nitroxynil and nitroscanate);benzenedisulphonamides (e.g., clorsulon); pyrazineisoquinolines (e.g.,praziquantel and epsiprantel); heterocyclic compounds (e.g., piperazine,diethylcarbamazine, dichlorophen, and phenothiazine); arsenicals (e.g.,thiacetarsamide, melorsamine, and arsenamide); cyclooctadepsipeptides(e.g., emodepside, PF1022A); paraherquamides (e.g., derquantel,paraherquanide); and amino-acetonitrile compounds (e.g. monepantel, AAD1566); tribendimidine (amidine compound); amidine compounds (e.g.,amidantel and tribendimidin), including all pharmaceutically acceptableforms, such as salts, solvates or N-oxides.

The compounds as described in this specification can be combined withpharmaceutically acceptable insecticides or acaricides. Suchpharmaceutically acceptable insecticides and acaricides include, forexample, acetamiprid, acetoprole, amitraz, amidoflumet, avermectin,azadirachtin, bifenthrin, bifenazate, broflanilide, buprofezin,bistrifluron, chlorfenapyr, chlorfluazuron, chlorantraniliprole,chlorpyrifos, chromafenozide, clothianidin, cyantraniliprole,cyflumetofen, 13-cyfluthrin, cyhalothrin, Acyhalothrin, cymiazolecypermethrin, cyromazine, deltamethrin, demiditraz, diafenthiuron,diazinon, diflubenzuron, dimefluthrin, dinotefuran, emamectin,esfenvalerate, ethiprole, fenoxycarb, fenpropathrin, fenvalerate,fipronil, flonicamid, flubendiamide, flucythrinate, tau-fluvalinate,flufenoxuron, halofenozide, hexaflumuron, imidacloprid, indoxacarb,lufenuron, metaflumizone, methoprene, metofluthrin, methoxyfenozide,nitenpyram, novaluron, noviflumuron, permethrin, phosmet, profluthrin,protrifenbute, pymetrozine, pyrafluprole, pyrethrin, pyridalyl,pyrifluquinazon, pyriprole, pyriproxyfen, rotenone, ryanodine,sisapronil, spinetoram, spinosad, spirodiclofen, spiromesifen,spirotetramat, sulfoxaflor, tebufenozide, tebufenpyrad, teflubenzuron,tefluthrin, tetrachlorvinphos, tetramethylfluthrin, thiacloprid,thiamethoxam, tigolaner, tolfenpyrad, tralomethrin, and triflumuron.General references discussing antiparasitic agents, such as insecticidesand acaricides, include, for example, The Pesticide Manual, 18thEdition, J. A. Turner, Ed., British Crop Protection CouncilPublications, U.K. (2018).

The compounds as described in this specification can be combined withpharmaceutically acceptable insect growth regulators. Suchpharmaceutically acceptable insect growth regulators include, forexample, methoprene, pyriproxyfen, tetrahydroazadirachtin,chlorfluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron,flufenoxuron, hexaflumuron, lufenuron, ifenuron, tebufenozide, andtriflumuron. These compounds tend to provide both initial and sustainedtreatment of parasite infections at all stages of insect development,including eggs, on the animal subject, as well as within the environmentof the animal subject.

The compounds as described in this specification can be combined withpharmaceutically acceptable anti-protozoals. Such pharmaceuticallyacceptable anti-protozoals include, for example, triazintriones like,for example, toltrazuril and ponazuril and triazindiones such asclazuril, diclazuril and letrazuril. In some contemplated embodiments,the compounds are administered with dihydroazole compounds, such as, forexample, compounds discussed in WO 2010/75591.

In some contemplated embodiments, the compounds of the present inventionare administered with anthelminic proteins, such as, for exampleBacillus thuringensis crystal proteins e.g. described in WO 2010/053517.

In some contemplated embodiments, the compounds are administered withpyridylmethylamine derivatives, such as, for example, pyridylmethylaminederivatives discussed in EP0539588 WO2007/115643.

In some contemplated embodiments, the compounds is administered withnodulisporic acids and derivatives thereof, such as, for example,compounds discussed in U.S. Pat. Nos. 5,399,582; 5,945,317; 5,962,499;5,834,260; 6,221,894; or U.S. Pat. No. 5,595,991; or WO1996/29073.

In some contemplated embodiments, the compounds are administered withisoxazoline compounds (e.g., sarolaner, fluralaner, lotilaner,afoxolaner, fluxametamide, isocycloseram)

Other antiparasitic compounds contemplated to be useful in combinationtherapies with the compounds include, for example, imidazo[1,2-b]pyridazine compounds discussed in US2005-0182059; 1-(4-Mono anddihalomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compoundsdiscussed U.S. Pat. No. 7,361,689; trifluoromethanesulfonanilide oximeether compounds discussed in U.S. Pat. No. 7,312,248;n-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide andn-[(phenylsulfanyl)phenyl]-1, 1,1-trifluoromethanesulfonamide compoundsdiscussed in US2006-0281695; and2-phenyl-3-(1H-pyrrol-2-yl)acrylonitrile compounds discussed inUS2006/0128779; azole compounds discussed in WO2017/192385,WO2019/170626, WO2019/197468, WO2019/201835, WO2019/206799,WO2019/215198, WO2020/053364, WO2020/053365, WO2020/070049,WO2020/079198, WO2020/094363, WO2020/169445, WO2020/193341,WO2020/201079, WO2020/201398, WO2020/208036, WO2020/212235, andWO2020/219871.

In embodiment 1 the present invention is directed to a compound ofFormula (I)

-   -   wherein    -   R¹ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR²R³, COOH, C(═O)OR⁴, SR⁴, SOR⁴, SO₂R⁴, SO₂NR⁵R⁶            and C(═O)NR⁵R⁶,            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, NR^(2′)R^(3′),                    C(═O)OR^(4′), SR^(4′), SOR^(4′), SO₂R^(4′),                    SO₂NR^(5′)R^(6′) and C(═O)NR^(5′)R^(6′),    -   R² and R³ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R² and R³ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R² and R³            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(2″)R^(3″), C(═O)OR^(4″), SR⁴″, SOR⁴, SO₂R^(4″),                SO₂NR^(5″)R^(6″) and C(═O)NR^(5″)R⁶″,    -   R⁴, R⁵ and R⁶ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(2′), R^(3′), R^(4′), R^(5′) and R^(6′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(2″), R^(3″), R^(4″), R^(5″) and R^(6″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R⁷ is independently selected from the group consisting of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀            aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,            C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,            mercapto, NR⁸R⁹, COOH, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰,            SO₂NR¹¹R¹² and C(═O)NR¹¹R¹²            -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀                aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy or                C₁₋₆-alkylmercapto, is optionally substituted with one                or more substituent(s) independently selected from the                group consisting of                -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                    C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                    C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                    C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,                    nitro, hydroxy, mercapto, oxo, NR⁸R^(9′),                    C(═O)OR^(10′), SR^(10′), SOR^(10′), SO₂R^(10′),                    SO₂NR^(11′)R^(12′) and C(═O)NR¹¹R¹²,    -   R⁸ and R⁹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl, or    -   R⁸ and R⁹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,            C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,            C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with            C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substituted with 5- to            10-membered heterocyclyl, C₁₋₆-alkyl substituted with            C₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered            heteroaryl or the heterocyclic ring formed by R⁸ and R⁹            together with the N atom to which they are attached is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(8″)R^(9″), C(═O)OR^(10″), SR^(10″), SOR¹⁰—, SO₂R¹⁰—,                SO₂NR^(11″)R^(12″) and C(═O)NR^(11″)R^(12″),    -   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R¹³ is hydrogen or C₁₋₃ alkyl,    -   R¹⁴ is hydrogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, NR^(14′)R^(14″),        wherein R^(14′) and R^(14″) are independently C₁₋₃-alkyl or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or 1R¹³ and R¹⁴ together with the atoms to which        they are attached form a 5 or 6-carbon atoms containing        unsaturated ring, wherein the unsaturated ring is optionally        substituted with one or more C₁₋₃-alkyl, and/or wherein one or        more of the ring-forming carbon atoms are optionally replaced by        —NH—, —N═, ═N—, —O— or —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(15′)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16′), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(17′)R^(17″), wherein R^(17′) and        R^(17″) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen        C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R^(18″), wherein R^(18′) and        R^(18″) are independently C₁₋₃-alkyl,    -   R¹⁹ is independently selected from the group consisting of        C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5- to                10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered                heteroaryl, C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen,                cyano, nitro, hydroxy, mercapto, NR²⁰R²¹, C(═O)OR²²,                SR²², SOR²², SO₂R²², SO₂NR²³R²⁴ and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to            10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁-C₆-alkyl            substituted with C₆₋₁₀-aryl, C₁₋₆-alkyl substituted with 5-            to 10-membered heteroaryl, or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5-            to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered            heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto or the            heterocyclic ring formed by R²⁰ and R²¹ together with the N            atom to which they are attached is optionally substituted            with one or more substituents independently selected from            the group consisting of            -   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,                C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,                C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy,                carbonyl, halogen, cyano, hydroxy, mercapto,                NR^(20′)R^(21′), C(═O)OR^(22′) SR^(22′), SOR^(22′),                SO₂R^(22′), SO₂NR^(23′)R^(24′) and C(═O)NR^(23′)R^(24′),    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl,    -   R²⁵ is independently selected from hydrogen and C₁₋₆-alkyl,    -   or a stereoisomer, physiologically acceptable salt, ester,        solvate, polymorph, prodrug and mixtures thereof.

In embodiment 2 the present invention is directed to a compoundaccording to embodiment 1, wherein R¹ is independently selected from thegroup consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro,        hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituents independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy                and NR^(2′)R^(3′),

-   R² and R³ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to        10-membered heteroaryl, or

-   R² and R³ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3 further    ring atoms are selected from N, S and O,    -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5 to        10-membered heteroaryl or the heterocyclic ring formed by R² and        R³ together with the N atom to which they are attached is        optionally substituted with one or more substituent(s)        independently selected from the group consisting of        -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy,

-   R⁴, R⁵ and R⁶ are independently selected from hydrogen and    C₁₋₆-alkyl,

-   R^(2′) and R^(3′) are independently selected from hydrogen and    C₁₋₆-alkyl.

In embodiment 3 the present invention is directed to a compoundaccording to embodiment 1 or 2, wherein R¹ is independently selectedfrom the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy and halogen,        -   wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy and                NR^(2′)R^(3′),

-   wherein R^(2′) and R^(3′) are independently selected from hydrogen    and C₁₋₃-alkyl.

In embodiment 4 the present invention is directed to a compoundaccording to anyone of embodiments 1 to 3, wherein R¹ is independentlyselected from the group consisting of

-   -   hydrogen, methyl, trifluoromethyl, ethyl, methoxy, ethoxy,        fluoride and chloride, preferably selected from the group        consisting of hydrogen, and methyl.

In embodiment 5 the present invention is directed to a compoundaccording to any one of embodiments 1 to 4, wherein R⁷ is independentlyselected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4- to 10        membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,        NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and C(═O)NR¹¹R¹²,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4-            to 10 membered heterocyclyl or C₁₋₆-alkoxy is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10 membered                heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,                NR^(8′)R^(9′), C(═O)OR^(10′), and C(═O)NR^(11′)R^(12′),

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to 10        membered heterocyclyl and 5- to 10 membered heteroaryl, or

-   R⁸ and R⁹ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further    ring atoms are selected from N, S and O;    -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to 10        membered heterocyclyl, and 5- to 10 membered heteroaryl or the        heterocyclic ring formed by R⁸ and R⁹ together with the N atom        to which they are attached is optionally substituted with one or        more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy,            NR^(8″)R^(9″), C(═O)—OR^(10″) and C(═O)NR^(11″)R^(12″);

-   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen and    C₁₋₆-alkyl,

-   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently    selected from hydrogen and C₁₋₆-alkyl,

-   R^(8″), R^(9″), R^(10″), R^(11″) and R^(12″) are independently    selected from hydrogen and C₁₋₆-alkyl.

In embodiment 6 the present invention is directed to a compoundaccording to any one of embodiments 1 to 5, wherein R⁷ is independentlyselected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰,        SOR¹⁰, SO₂R¹⁰ and C(═O)NR¹¹R¹²,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₆-alkyl, 5- to 10 membered heterocyclyl, C₁₋₆-alkoxy,                halogen, cyano, hydroxy, oxo, NR^(8′)R^(9′),                C(═O)OR^(10′) and C(═O)NR^(11′)R^(12′),

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl, and 5- to 10        membered heteroaryl, or

-   R⁸ and R⁹ together with the N atom to which they are attached form a    saturated or unsaturated heterocyclic ring having 3 to 12 ring    atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3 further    ring atoms are selected from N, S and O;    -   wherein the C₁₋₆-alkyl, C₆₋₁₀-aryl, and 5- to 10 membered        heteroaryl or the heterocyclic ring formed by R⁸ and R⁹ together        with the N atom to which they are attached is optionally        substituted with one or more substituent(s) independently        selected from the group consisting of        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy and NR^(8″)R⁹″,

-   R¹⁰, R¹¹ and R¹² are independently selected from hydrogen or    C₁₋₆-alkyl,

-   R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) are independently    selected from hydrogen or C₁₋₆-alkyl.

-   R^(8″) are R^(9″) are independently selected from hydrogen or    C₁₋₆-alkyl.

In embodiment 7 the present invention is directed to a compoundaccording to any one of embodiments 1 to 6, wherein R⁷ is independentlyselected from the group consisting of

-   -   hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered        heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹,        -   wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered            heterocyclyl or C₁₋₆-alkoxy is optionally substituted with            one or more substituent(s) independently selected from the            group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and halogen,

-   R⁸ and R⁹ are independently selected from the group consisting of    -   hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        -   wherein the C₁₋₆-alkyl, or C₃₋₆-cycloalkyl is optionally            substituted with one or more substituent(s) independently            selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.

In embodiment 8 the present invention is directed to a compoundaccording to any one of embodiments 1 to 7, wherein R⁷ is independentlyselected from the group consisting of

-   -   methyl, ethyl, isopropyl, isopropenyl, methoxy, ethoxy,        isopropoxy, hydroxy, methyl sulfoxyl, methyl sulfonyl,        methylthio, amino, methylamino, ethylamino, isopropylamino,        dimethylamino, isopropylmethylamino, cyclopropylamino,        2-hydroxyethylmethylamino, hydroxyethylamino, methoxyethylamino,        morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxy-pyrrolidin-1-yl, 3-fluoroazetidin-1-yl and        3,3-difluoroazetidin-1-yl, 4-oxo-1-piperidyl, azetidin-1-yl,        tetrahydro-2H-pyran-4-yl, piperidin-1-yl, and        4,4-difluoropiperidin-1yl.

In embodiment 9 the present invention is directed to a compoundaccording to any one of embodiments 1 to 8, wherein

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        the saturated ring is optionally substituted with one or more        C₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —O—, —S(O)—,        —S(O)₂— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        the unsaturated ring is optionally substituted with one or more        C₁₋₃-alkyl, and/or wherein one or more of the ring-forming        carbon atoms are optionally replaced by —NH—, —N═, ═N—, —O— or        —S—,    -   A1 is N or CR¹⁵, wherein R¹⁵ is independently hydrogen, halogen        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15″)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl,    -   A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is N or CR¹⁷, wherein R¹⁷ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15″)R^(15″), wherein R^(15′) and        R^(15′) are independently C₁₋₃-alkyl,    -   A4 is N or CR¹⁸, wherein R¹⁸ is independently hydrogen, halogen,        C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15″)R^(15″), wherein R^(15′) and        R^(15″) are independently C₁₋₃-alkyl.

In embodiment 10 the compound according to any one of embodiments 1 to9, wherein

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—, or    -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing unsaturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —N═, ═N—, —O— or —S—,    -   A1 is CR¹⁵ wherein R¹⁵ is independently hydrogen, halogen C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(5′)R¹, wherein R^(15′) and R^(15″) are        independently C₁₋₃-alkyl,    -   A2 is CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen, C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is CR¹⁷, wherein R¹⁷ is hydrogen,    -   A4 is CR¹⁸, wherein R¹⁸ is hydrogen.

In embodiment 11 the compound according to any one of embodiments 1 to10, wherein

-   -   R¹³ and R¹⁴ together with the atoms to which they are attached        form a 5 or 6-carbon atoms containing saturated ring, wherein        one or more of the ring-forming carbon atoms are optionally        replaced by —NH—, —O— or —S—,    -   A1 is CR¹⁵ wherein R¹⁵ is independently hydrogen, halogen C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(5′)R¹, wherein R^(15′) and R^(15″) are        independently C₁₋₃-alkyl,    -   A2 is CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen, C₁₋₃        alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) and        R^(16″) are independently C₁₋₃-alkyl,    -   A3 is CR¹⁷, wherein R¹⁷ is hydrogen,    -   A4 is CR¹⁸, wherein R¹⁸ is hydrogen.

In embodiment 12 the present invention is directed to a compoundaccording to any one of embodiments 1 to 11, wherein none, one or two ofresidues A1, A2, A3 and A4 is N.

In embodiment 13 the present invention is directed to a compoundaccording to any one of embodiments 1 to 12, wherein R¹⁹ isindependently selected from the group consisting of

-   -   R¹⁹ is independently selected from the group consisting of    -   C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered                heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy, NR²⁰R²¹,                C(═O)OR²² and C(═O)NR²³R²⁴    -   R²⁰ and R²¹ are independently selected from the group consisting        of        -   hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl or    -   R²⁰ and R²¹ together with the N atom to which they are attached        form a saturated or unsaturated heterocyclic ring having 3 to 12        ring atoms, wherein 0, 1, 2, or 3 further ring atoms are        selected from N, S and O;        -   wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl C₁₋₆-alkoxy, or            C₆₋₁₀-aryl or the heterocyclic ring formed by R²⁰ and R²¹            together with the N atom to which they are attached is            optionally substituted with one or more substituents            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered                heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,                C₁₋₆-alkoxy, halogen, cyano, hydroxy, NR^(20′)R^(21′),                C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′)    -   R²², R²³ and R²⁴ are independently selected from hydrogen and        C₁₋₆-alkyl,    -   R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independently        selected from hydrogen and C₁₋₆-alkyl.

In embodiment 14 the present invention is directed to a compoundaccording to any one of embodiments 1 to 13, wherein R¹⁹ isindependently selected from the group consisting of

-   -   C₆₋₁₀-aryl and 5- to 10-membered heteroaryl        -   wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is            optionally substituted with one or more substituent(s)            independently selected from the group consisting of            -   C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and                hydroxy,            -   wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally                substituted with one or more substituents independently                selected from the group consisting of halogen, cyano,                hydroxy, preferably each C₁₋₆-alkyl, C₁₋₆-alkoxy, is                optionally substituted with one or more halogen.

In embodiment 15 the present invention is directed to a compoundaccording to any one of embodiments 1 to 14, wherein R¹⁹ is C₆₋₁₀-aryl,

-   -   wherein the C₆₋₁₀-aryl is optionally substituted with one or        more substituent(s) independently selected from the group        consisting of        -   C₁₋₆-alkyl, halogen, C₁₋₆-alkoxy cyano and nitro wherein            each C₁₋₆-alkyl, C₁₋₆-alkoxy is optionally substituted with            one or more halogen.

In embodiment 16 the present invention is directed to a compoundaccording to any one of embodiments 1 to 14, wherein R¹⁹ is C₆₋₁₀-aryl,

-   -   wherein the C₆₋₁₀-aryl is phenyl substituted with one, two or        three substituents independently selected from the group        consisting of

-   fluoride, chloride bromide, trifluoromethyl and trifluoromethoxy.

In embodiment 17 the present invention is directed to a compoundaccording to any one of embodiments 1 to 16, wherein R²⁵ is hydrogen.

In embodiment 18 the present invention is directed to a compoundaccording to any one of the embodiments as described herein beingpresent in form of the (S)-enantiomer.

In embodiment 19 the present invention is directed to a process forpreparing the compound according to Formula (I) comprising the step of

-   -   reacting a compound of Formula (A)

-   -   with a compound of Formula (B)

wherein R¹, R⁷, R¹³, R¹⁴, A1, A2, A3, A4, R¹⁹ and R²⁵ are defined as inany one of embodiments as described herein, to obtain the compoundaccording to Formula (I).

In embodiment 20 the present invention is directed to a veterinarycomposition comprising

-   -   compound according to Formula (I) according to any one of        embodiments as described herein, and    -   one or more physiologically acceptable excipient(s).

In embodiment 21 the present invention is directed to a veterinarycomposition according to embodiment 20, wherein the one or morephysiologically acceptable excipient(s) are selected from carriers,fillers, flavours, binders, antioxidants, buffers, sugar components,lubricants, surfactants, stabilizers, flow agents, disintegration agentsand preservatives and mixtures thereof.

In embodiment 22 the present invention is directed to a compoundaccording to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one of theembodiments as described herein for use as a medicament.

In embodiment 23 the present invention is directed to a compoundaccording to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one ofembodiments as described herein for use in the treatment ofdisorders/diseases caused by helminths.

In embodiment 24 the present invention is directed to a compoundaccording to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one ofembodiments as described herein for use according to embodiment 23,wherein the disease is the heartworm disease.

In embodiment 25 the present invention is directed to a compoundaccording to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one ofembodiments as described herein for use according to embodiment 23 or24, wherein the helminths are Dirofilaria immitis.

In embodiment 26 the present invention is directed to a method oftreating a disease caused by helminths which comprises administering toan animal, in particular a dog, a therapeutically effective amount of acompound according to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one ofembodiments as described herein.

In embodiment 27 the present invention is directed to a method oftreating filariasis and especially heartworm disease comprisingadministering a therapeutically effective amount of a compound accordingto Formula (I) according to any one of embodiments as described hereinor a veterinary composition according to any one of embodiments asdescribed herein to a mammal, in particular a dog, in need thereof.

In embodiment 28 the present invention is directed to a method fortreating an animal with diseases caused by a nematode comprisingadministering to the subject in need thereof an effective amount of acompound according to Formula (I) according to any one of embodiments asdescribed herein or a veterinary composition according to any one ofembodiments as described herein, wherein the helminth is a nematode andis at least one selected from the group of Dirofilaria spp., inparticular Dirofilaria immitis. Suitably the subject is a mammal, inparticular a dog or a cat, especially a dog.

In embodiment 29 the present invention is directed to a method fortreating a mammal, preferably a dog, suffering from a disease caused bya helminth, in particular a nematode, comprising administering to thesubject in need thereof an effective amount of a compound according toFormula (I) according to any one of embodiments as described herein or aveterinary composition according to any one of embodiments as describedherein, wherein the nematode is at least one selected from the group ofDirofilaria, in particular Dirofilaria immitis.

Features of the invention have been described in embodiments in thepresent application; however, for brevity not all combinations of thefeatures are literally described. Combinations of features as describedabove are, however, expressly considered to be part of the invention.

EXPERIMENTAL PART Analytics—HPLC Methods Method 1 ChromatographicSystem:

Column: Xbridge BEH C18 Waters, 2.1×50 mm, 2.5μ

Oven: 40° C.

Eluents: Solvent A: water/HCO₂H (0.05%); Solvent B: acetonitrile/HCO₂H(0.05%)

Flow: 0.8 ml/min

Gradient:

Time Solvent A Solvent B [min] [%] [%] 0.0 98 2 1.2 0 100 1.7 0 100 1.898 2

Run time: 2.2 min+0.5 min equilibration time

Method 2 Chromatographic System:

Column: Xbridge BEH C18 Waters, 2.1×50 mm, 2.5μ

Oven: 40° C.

Eluents: Solvent A: water/NH₃ (0.1%); Solvent B: acetonitrile

Flow: 0.8 ml/min

Gradient:

Time Solvent A Solvent B [min] [%] [%] 0.0 98 2 1.2 0 100 1.7 0 100 1.898 2

Run time: 2.2 min+0.5 min equilibration time

Method 3 Chromatographic System:

Column: Xbridge BEH Phenyl Waters, 2.1×50 mm, 2.5μ

Oven: 40° C.

Eluents: Solvent A: water/HCO₂H (0.05%); Solvent B: acetonitrile/HCO₂H(0.05%)

Flow: 0.8 ml/min

Gradient:

Time Solvent A Solvent B [min] [%] [%] 0.0 98 2 1.2 0 100 1.7 0 100 1.898 2

Run time: 2.2 min+0.5 min equilibration time

General Synthetic Procedures

The compounds of the current invention can be synthesized as shown inScheme 1 below:

A 3-amino-2-alkoxycarbonylthiophene 1-I is halogenated in the4-position, preferably brominated. This can be achieved by heating withhydrobromic acid in dimethyl sulfoxide or by treatment with NBS incarbon tetrachloride, optionally with the addition of a radicalinitiator like dibenzoyl peroxide. Thiophene compounds 1-I arecommercially available or can be synthesized as described in, forexample, Synth. Commun. 2014 (44), 1002-1006. The ester in the halocompound 1-II is hydrolyzed by treatment with aqueous base, for examplesodium or potassium hydroxide in water. Heating of the thiophenecarboxylic acid 1-III under acidic conditions, for example in acetic orhydrochloric acid gives, under decarboxylation, the amino thiophene1-IV. This is condensed with diethyl ethoxymethylenemalonate 1-V and theresulting enamine compound 1-VI is cyclized by heating, for example byrefluxing in a mixture of biphenyl and biphenylether (Dowtherm A) togive the thienopyridine 1-VII as described in US2004/0138449. Compounds1-III, 1-IV and 1-VI can be isolated, or the sequence of 1-III to 1-VIIcan be performed in one pot.

The 4-hydroxy group is activated, for example by converting to ahalogen, preferably a chloride by treatment with thionyl chloride.Alternatively, the hydroxy is esterified, for example by esterificationwith triflic acid anhydride. This is followed by treatment with anucleophile YR⁷ to yield the 4-substituted thienopyridine 1-VIII. Incase R⁷ is an amino substituent, YR⁷ is preferably an amine, in case R⁷is an alkoxy substituent, YR⁷ is preferably an alkoxide. A Suzuki-typecoupling with the boronic acid 1-IX as described in, for example,Tetrahedron 58(48), 9633-9695, 2002 gives 1-X. As an alternative to thefree boronic acid 1-IX an analogous boronic ester might be used, forexample a pinacol ester.

Ester hydrolysis by treatment with aqueous base gives the thienopyridinecarboxylic acid 1-XI. Amine 1-XIII is acylated with the thienopyridinecarboxylic acid 1-XI to give the amide 1-XIV. Acylation can be performedby activation of 1-X as acid chloride or use of a coupling reagent likeHATU or DCC followed by treatment with 1-XIII in the presence of a baselike triethylamine. Conditions for acylation reactions are described in,for example, volume E22a of Methods of Organic Chemistry (Houben-Weyl),Synthesis of Peptides and Peptidomimetics, 4 h edition, Georg ThiemeVerlag, Stuttgart-New York, 2002. 1-XIII can be a primary amine (R²⁵═H)or a secondary amine (R²⁵=alkyl), in the latter case R²⁵ can beintroduced by reductive amination of the primary amine 1-XII.

Alternatively, the thienopyridine 1-VIII can be subjected tosaponification followed by coupling with the amino compound 1-XIII togive the amide 1-XV as shown below:

Suzuki-type coupling with the boronic acid 1-IX gives the amide 1-XIV.

Alternatively, compounds of Formula I, for example where R⁷ is an alkylor alkenyl group, can be synthesized as shown in scheme 2.

4-Hydroxythienopyridine 1-VII undergoes a Suzuki-type coupling with aboronic acid 1-IX as described in Scheme 1 to yield 2-I. The 4-hydroxygroup is activated to give 2-II, for example by treatment with achlorinating agent like thionyl chloride (X═Cl) or phosphoryl bromide(X═Br) or by treatment with triflic acid anhydride (X═OSO₂CF₃). Theactivated 2-II is reacted with an alkyl- or alkenyl boronic acid 2-IIIas described in, for example, Chem Med Chem, 2014, 9(4), 719-723followed by saponification with aqueous base to give the carboxylic acid1-XI. Acylation of the amine 1-XIII with 1-XI as described in Scheme 1gives the amide 1-XIV.

Alternative reaction sequences are also possible, for example whereactivation of 1-VII is followed by Suzuki-type coupling to give theester 1-VIII. This can then be coupled with the boronic acid 1-IX togive the ester 1-X. Or 1-VIII can be subjected to saponificationfollowed by amide coupling to give 1-XV which upon Suzuki-type couplingwith 1-IX gives compound 1-XIV.

An activated ester compound 2-IV can be alkylated with another estercompound like 3-I, for example when R⁷ represents a cycloalkyl orheterocycloalkyl like a tetrahydropyran (Scheme 3). In the presence of abase like LDA or LHMDS 3-I is deprotonated in the position alpha to theester group and can substitute X in 2-IV. Saponification by aqueous basefollowed by decarboxylation as described in, for example, WO2019/215182leads to the acid 3-III that can be coupled with the amine 1-XIIIfollowed by a Suzuki-type coupling with 1-IX to give the amide 1-XIV.

Synthetic Procedures—Specific Compounds Synthesis of(S)—N-(chroman-4-yl)-3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxamide(Example 4)

1. Methyl 3-amino-4-bromothiophene-2-carboxylate

Methyl 3-aminothiophene-2-carboxylate (25.7 g, 163 mmol) was dissolvedin DMSO (35 ml). At 20° C. hydrogen bromide (18.50 ml, 163 mmol) wasadded and the solution was stirred at 90° C. for 3 h and then at 100° C.for 20 h. The reaction mixture was diluted with 500 ml aqueous sodiumhydrogen carbonate (5%) and extracted twice with dichloromethane (500ml). The combined extracts were washed with 2×500 ml water, dried overNa₂SO₄, filtered and evaporated. The residue was purified bychromatography (silica, eluting with a gradient of n-pentane/ethylacetate) to yield a solid. MS: 237.9 (M+1).

2. Diethyl 2-(((4-bromothiophen-3-yl)amino)methylene)malonate

Methyl 3-amino-4-bromothiophene-2-carboxylate (6.10 g, 25.8 mmol) wasdissolved in ethanol (20 ml). Aqueous sodium hydroxide (1M, 31.0 ml) wasadded and the mixture was stirred at 90° C. for 0.5 h. After cooling toroom temperature acetic acid (2 ml) was added and the mixture wasstirred at 90° C. for 0.5 h. After cooling to room temperature, diethylethoxymethylenemalonate (5.22 ml, 25.8 mmol) was added and the resultingmixture was stirred overnight at room temperature. It was diluted with300 ml water, the precipitate was isolated by filtration and washed with3×100 ml water to give the product as a solid. MS: 349 (M+1).

3. Ethyl 3-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate

Dowtherm A (40 ml) was heated to reflux (260° C.). Diethyl2-(((4-bromothiophen-3-yl)amino)methylene)malonate (8.2 g, 23.55 mmol)was added and the mixture was stirred at 260° C. for 45 min. Aftercooling to 90° C. n-heptane was added (300 ml). After further cooling to23° C. (room temperature), the precipitate was isolated by filtrationand washed with 2×100 ml n-heptane. The resulting solid was suspended in70 ml ethyl acetate, filtered and washed with 70 ml ethyl acetatefollowed by 70 ml n-heptane to give the product as a solid. MS: 303.9(M+1).

4. Ethyl 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carboxylate

Ethyl 3-bromo-7-hydroxythieno[3,2-b]pyridine-6-carboxylate (2.80 g, 9.27mmol) was suspended in chloroform (28 ml). A small drop DMF and thienylchloride (0.812 ml, 11.12 mmol) were added and the mixture was stirredunder reflux for 40 h. After cooling to 23° C. (room temperature) themixture was slowly added to 80 ml saturated aqueous sodium hydrogencarbonate solution, and extracted with 50 ml dichloromethane. Theextract was dried over Na₂SO₄, filtered and evaporated. The resultingresidue was purified first by chromatography (silica, eluting with agradient of n-pentane/ethyl acetate) and afterwards by stirring the rawproduct with a mixture of 50 ml ethyl acetate and 100 ml n-pentane.After 2 h the solid was isolated by filtration and washed with 100 mln-pentane to give the product as a solid. MS: 321.9 (M+1)

5. Ethyl 3-bromo-7-morpholinothieno[3,2-b]pyridine-6-carboxylate

Ethyl 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carboxylate (0.435 g, 1.36mmol) was dissolved in morpholine (5.0 ml, 58.0 mmol) and the mixturewas stirred at 23° C. (room temperature) for 1 h. Dichloromethane (30ml) was added, the mixture was washed with water (3×100 ml) andconcentrated under reduced pressure. The residue was purified bychromatography (silica, eluting with a gradient of n-pentane/ethylacetate) to give the product as a solid. MS: 373.0 (M+1).

6. Ethyl3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxylate

Ethyl 3-bromo-7-morpholinothieno[3,2-b]pyridine-6-carboxylate (0.5 g,1.35 mmol), (3,5-dichlorophenyl)boronic acid (540 mg, 2.83 mmol) andpotassium carbonate (465 mg, 3.37 mmol) were combined under argon withdioxane (20 ml) and water (10 ml). Pd(PPh₃)₄ (78 mg, 0.067 mmol) wasadded and the mixture was stirred for 60 min at 90° C. Afterwards themixture was extracted with dichloromethane (2×50 ml), the combinedextracts were concentrated under reduced pressure and the residue waspurified by chromatography (silica, eluting with a gradient ofn-pentane/ethyl acetate). The product was obtained as a solid. MS: 437.0(M+1).

7. 3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxylicacid

Ethyl3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxylate(530 mg, 1.21 mmol) and lithium hydroxide hydrate (530 mg, 13.06 mmol)were combined with water (5.5 ml) and 2-methyltetrahydrofuran (5.5 ml)and the mixture was stirred at 90° C. After 30 min additional2-methyltetrahydrofuran (5.5 ml) was added and stirring was continued at90° C. After 24 h 1,4-dioxane (5.3 ml) was added, stirring was continuedat 110° C. for 6 hours. The mixture was cooled to room temperature andHCl (1M, 13 ml) was added. The mixture was concentrated under reducedpressure and the residue obtained was used as such in the next step. MS:409.0 (M+1)

8.(S)—N-(chroman-4-yl)-3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxamide

Thionyl chloride (2 ml, 27.4 mmol) was added to a stirred mixture of3-(2,3-dichlorophenyl)-7-morpholinothieno[3,2-b]pyridine-6-carboxylicacid (152 mg, 0.371 mmol) and a small drop DMF in dichloromethane (4 ml)and the mixture was stirred at room temperature. After 45 min additionalthionyl chloride (1 ml, 13.70 mmol) was added and stirring was continuedovernight. The mixture was concentrated under reduced pressure,dichloromethane (4 ml), triethylamine (0.13 ml, 0.93 mmol) and(S)-chroman-4-amine hydrochloride (83 mg, 0.45 mmol) were added and themixture was stirred at room temperature overnight. Water (10 ml) anddichloromethane (10 ml) were added, the phases were separated and theaqueous phase was extracted again with dichloromethane. The combinedorganic phases were concentrated under reduced pressure, and the residuewas purified by chromatography (silica, eluting with a gradient ofn-pentane/ethyl acetate). The obtained solid residue was stirred for 5min in a 1:2 mixture of ethyl acetate and n-pentane (5 ml), filtered andwashed with a 1:2 mixture of ethyl acetate and n-pentane (2×5 ml)followed by n-pentane (5 ml). The product was obtained as a solid. MS:540.1 (M+1).

Synthesis of(S)—N-(chroman-4-yl)-3-(2,3-dichlorophenyl)-7-dimethylamino-2-methylthieno[3,2-b]pyridine-6-carboxamide(example 36)

1. Methyl 3-amino-4-bromo-5-methylthiophene-2-carboxylate

Methyl 3-amino-5-methylthiophene-2-carboxylate (53.8 g, 314 mmol) wasdissolved in acetonitrile (1047 ml) and stirred at 50° C. NBS (67.1 g,377 mmol) was added in portions and stirring was continued for 45 min.The reaction mixture was quenched by addition of saturated aqueousNa₂SO₃ and extracted with EtOAc (2×10 mL). The combined extracts werewashed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica, gradient n-pentane/EtOAc 100:1 to 80:20) toyield a yellow solid. MS: 250.2 (M+1).

2. Diethyl 2-(((4-bromo-5-methylthiophen-3-yl)amino)methylene)malonate

A 1 L flask was charged with methyl3-amino-4-bromo-5-methylthiophene-2-carboxylate (45.5 g, 182 mmol) andethanol (182 ml). Sodium hydroxide (1 M, 218 ml) was added and themixture was heated to 90° C. After two hours heating was stopped and themixture was allowed to reach room temperature and then cooled to 0° C.Acetic acid (15.79 ml, 273 mmol) was added to give a white turbidmixture, which was heated to 90° C. After 90 min the mixture was allowedto reach room temperature, diethyl ethoxymethylenemalonate (36.8 ml, 182mmol) was added and the resulting turbid mixture was stirred overnightat ambient temperature. The resulting precipitate was isolated byfiltration, washed with water (500 mL) and EtOH (100 mL) to give ayellow solid, which was dried under reduced pressure. MS: 364.0 (M+1).

3. Ethyl 3-bromo-7-hydroxy-2-methylthieno[3,2-b]pyridine-6-carboxylate

Dowtherm A (300 ml) was heated to 260° C. in a 250 mL round-bottomflask. Diethyl2-(((4-bromo-5-methylthiophen-3-yl)amino)methylene)malonate (58.7 g, 162mmol) was added carefully into the hot solution and stirring wascontinued at 260° C. After 3 hours the mixture was cooled to 90° C.,transferred into an Erlenmeyer flask, diluted with n-heptane (300 mL)and stirred at room temperature for 1 hour. The resulting precipitatewas isolated by filtration, washed with n-pentane (5×100 mL) and theresulting solid was dried under reduced pressure. MS: 316.3 (M+1).

4. Ethyl 3-bromo-7-chloro-2-methylthieno[3,2-b]pyridine-6-carboxylate

A 500 mL flask was charged with ethyl3-bromo-7-hydroxy-2-methylthieno[3,2-b]pyridine-6-carboxylate (21.8 g,69.0 mmol) and chloroform (200 ml). DMF (0.02 ml) and thionyl chloride(10.06 ml, 138 mmol) were added, the mixture was heated to reflux andstirred overnight. The mixture was allowed to cool to room temperatureand concentrated under reduced pressure. The residue was dissolved indichloromethane, washed with saturated aqueous NaHCO₃ and brine, driedover MgSO₄ and concentrated under reduced pressure. The residue waspurified by column chromatography (silica, gradient of n-pentane/EtOAc100:1 to 2:1) to yield a solid. MS: 334.3 (M+1).

5. Ethyl3-bromo-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxylate

A 50 mL flask was charged with ethyl3-bromo-7-chloro-2-methylthieno[3,2-b]pyridine-6-carboxylate (2.0 g, 6.0mmol) and chloroform (20 ml). Triethylamine (1.25 ml, 9.0 mmol) followedby dimethylamine (2M in THF, 4.50 ml, 9.00 mmol) were added and themixture was heated to 85° C. Stirring was continued for 8 hours at 85°C., then heating was stopped and stirring was continued overnight. Themixture was poured into water (300 mL) and the layers were separated.The aqueous layer was extracted with dichloromethane (3×100 mL). Thecombined organic phases were washed with water and brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (silica, gradient of DCM/EtOAc 100:1 to 80:20)to yield an oil. MS: 343.3 (M+1).

6. 3-Bromo-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxylicacid

Ethyl3-bromo-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxylate(3.60 g, 10.5 mmol) and lithium hydroxide (2.012 g, 84 mmol) weredissolved in a mixture of 1,4-dioxane (31.5 ml) and water (10.5 ml) andthe resulting mixture was heated to 110° C. After stirring for 3 hoursat this temperature the mixture was allowed to reach room temperature.Concentrated hydrochloric acid (8.75 ml, 105 mmol) was added dropwise at0° C. and the mixture was stirred at room temperature overnight. Themixture was concentrated under reduced pressure, the residue wassuspended in cold THF and the resulting precipitate was isolated byfiltration to give a solid. MS: 316 (M+1).

7.(S)-3-bromo-N-(chroman-4-yl)-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxamide

A 100 mL flask was charged with3-bromo-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxylicacid (1.779 g, 5.25 mmol) in dichloromethane (26.2 ml) and DMF (0.026ml). Oxalyl chloride (2.298 ml, 26.3 mmol) was added at 0° C. and themixture was stirred at room temperature. After 3 hours additional oxalylchloride (2.298 ml, 26.3 mmol) was added at 0° C. and the mixture wasstirred at room temperature for 3 days. The mixture was concentratedunder reduced pressure to yield crude acid chloride that was useddirectly. The crude acid chloride was suspended in dichloromethane (26ml), TEA was added (8.78 ml, 63.0 mmol) followed by (S)-chroman-4-aminehydrochloride (1.170 g, 6.30 mmol) and the resulting mixture was stirredat room temperature. After 3.5 hours the mixture was diluted with DCM,washed with saturated aqueous NaHCO₃ (3×50 mL) and brine, dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby column chromatography (silica, gradient of DCM/EtOAc 100:0 to 80:20)to yield a solid. MS: 446.4 (M+1).

8.(S)—N-(chroman-4-yl)-3-(2,3-dichlorophenyl)-7-dimethylamino-2-methylthieno[3,2-b]pyridine-6-carboxamide

A 20 mL vial was charged with(S)-3-bromo-N-(chroman-4-yl)-7-(dimethylamino)-2-methylthieno[3,2-b]pyridine-6-carboxamide(400 mg, 0.896 mmol), 2,3-dichlorophenylboronic acid (256 mg, 1.344mmol), tetrakis(triphenylphosphine)palladium (104 mg, 0.090 mmol) andsodium carbonate (304 mg, 2.87 mmol). The vial was evacuated andrefilled with Argon (3 cycles). A mixture of 1,4-dioxane (12 ml) andwater (3.00 ml) was purged with argon, added to the solids and theresulting slurry was heated to 100° C. with stirring. After 4 hours themixture was allowed to reach room temperature, poured into water andextracted several times with dichloromethane. The combined extracts werewashed with brine, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (silica,gradient of DCM/EtOAc 100:0 to 70:30) to yield a solid. MS: 512.5 (M+1).

Table A: Examples

Table A below provides for each of the exemplified compounds of Formula(I) the structure, wherein in all exemplified compounds A1 to A4 are CH.The nature of R¹³ can have the consequence that the adjacent carbon(marked *) becomes asymmetric. In this case “R/S” denotes the absoluteconfiguration at the asymmetric carbon marked with (*) in Formula (I).

TABLE A No R¹ R⁷ R¹³ R¹⁴ R/S R¹⁹ R²⁵ 1 H morpholin-4-yl —CH₂—CH₂—O— (S)3,5-dichlorophenyl H 2 H morpholin-4-yl CH₃ H (S) 3,5-dichlorophenyl H 3H morpholin-4-yl —CH₂—CH₂— (S) 3,5-dichlorophenyl H 4 H morpholin-4-yl—CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 5 H morpholin-4-yl CH₃ H (S)2,3-dichlorophenyl H 6 H morpholin-4-yl —CH₂—CH₂— (S) 2,3-dichlorophenylH 7 H dimethylamino —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 8 Hdimethylamino CH₃ H (S) 3,5-dichlorophenyl H 9 H dimethylamino —CH₂—CH₂—(S) 3,5-dichlorophenyl H 10 H dimethylamino —CH₂—CH₂—O— (S)2,3-dichlorophenyl H 11 H dimethylamino CH₃ H (S) 2,3-dichlorophenyl H12 H dimethylamino —CH₂—CH₂— (S) 2,3-dichlorophenyl H 13 Hmorpholin-4-yl —CH₂—CH₂—CH₂— (S) 2,3-dichlorophenyl H 14 Hmorpholin-4-yl =CH—CH=CH— 2,3-dichlorophenyl H 15 H morpholin-4-yl—CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 16 H morpholin-4-yl —CH₂—CH₂—(S) 2,3,5-trifluorophenyl H 17 H 4-methylpiperazin-1-yl —CH₂—CH₂—O— (S)2,3-dichlorophenyl H 18 H 4-methylpiperazin-1-yl —CH₂—CH₂—CH₂— (S)3,5-dichlorophenyl H 19 H 4-methylpiperazin-1-yl —CH₂—CH₂—O— (S)3,5-dichlorophenyl H 20 H 4-methylpiperazin-1-yl —CH₂—CH₂—O—2,3-dichlorophenyl H 21 H dimethylamino —CH₂—CH₂—CH₂— (S)2,3-dichlorophenyl H 22 H dimethylamino =CH—CH=CH— 2,3-dichlorophenyl H23 H dimethylamino —CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 24 Hmorpholin-4-yl —CH₂—CH₂—O— (S) 2,3-difluorophenyl H 25 H dimethylamino—CH₂—CH₂— (S) 2,3,5-trifluorophenyl H 26 H 3,3-difluoroazetidin-1-yl—CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 27 H 3,3-difluoroazetidin-1-yl—CH₂—CH₂—O— 2,3-dichlorophenyl H 28 H dimethylamino —CH₂—CH₂—O—2,3-dichlorophenyl H 29 H 4-methylpiperazin-1-yl —CH₂—CH₂— (S)3,5-dichlorophenyl H 30 H 4-methylpiperazin-1-yl —CH₂—CH₂—CH₂—3,5-dichlorophenyl H 31 H dimethylamino —CH₂—CH₂—CH₂— (S)3,5-dichlorophenyl H 32 H morpholin-4-yl —CH₂—CH₂—CH₂— (S)3,5-dichlorophenyl H 33 CH₃ dimethylamino —CH₂—CH₂— (S)3,5-dichlorophenyl H 34 CH₃ dimethylamino —CH₂—CH₂— (S)2,3-dichlorophenyl H 35 CH₃ dimethylamino —CH₂—CH₂—CH₂— (S)2,3-dichlorophenyl H 36 CH₃ dimethylamino —CH₂—CH₂—O— (S)2,3-dichlorophenyl H 37 CH₃ dimethylamino =CH—CH—CH— 2,3-dichlorophenylH 38 CH₃ dimethylamino —CH₂—CH₂—CH₂— (S) 3,5-dichlorophenyl H 39 H3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S) 2,3-dichlorophenyl H 40 H3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 41 H3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S) 2,3,5-trifluorophenyl H 42 Hmorpholin-4-yl —CH₂—CH₂—O— (S) 3- trifluoromethylphenyl H 43 Hmorpholin-4-yl —CH₂—CH₂—O— (S) 3-methoxyphenyl H 44 H morpholin-4-yl—CH₂—CH₂—O— (S) 2,3-dimethylphenyl H 45 H morpholin-4-yl —CH₂—CH₂—O— (S)3,5-difluorophenyl H 46 H dimethylamino —CH₂—CH₂—O— (S)2,3-difluorophenyl H 47 H dimethylamino —CH₂—CH₂—O— (S) 3- Htrifluoromethylphenyl 48 H dimethylamino —CH₂—CH₂—O— (S) 3-methoxyphenylH 49 H morpholin-4-yl =CH—CH=CH— 3,5-dichlorophenyl H 50 H dimethylamino=CH—CH=CH— 3,5-dichlorophenyl H 51 H dimethylamino —CH₂—CH₂—O— (S)3,5-difluorophenyl H 52 H 4-oxo-1-piperidyl —CH₂—CH₂—O— (S)3,5-dichlorophenyl H 53 CH dimethylamino —CH₂—CH₂—O— (S)3,5-dichlorophenyl H 54 CH₃ dimethylamino =CH—CH—CH— 3,5-dichlorophenylH 55 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—CH₂— (S) 2,3-dichlorophenylH 56 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H57 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S) 2,3-dichlorophenyl H 58CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—CH₂— (S) 3,5-dichlorophenyl H 59CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 60CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S) 3,5-dichlorophenyl H 61 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—CH₂— (S) 2,3-dichlorophenyl H 62 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 63 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂— (S) 2,3-dichlorophenyl H 64 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—CH₂— (S) 3,5-dichlorophenyl H 65 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 66 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂— (S) 3,5-dichlorophenyl H 67 CH₃morpholin-4-yl —CH₂—CH₂—CH₂— (S) 3,5-dichlorophenyl H 68 CHmorpholin-4-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 69 CH₃morpholin-4-yl —CH₂—CH₂— (S) 3,5-dichlorophenyl H 70 CH₃ morpholin-4-yl=CH-CH=CH- 3,5-dichlorophenyl H 71 CH₃ morpholin-4-yl —CH₂—CH₂—CH₂— (S)2,3-dichlorophenyl H 72 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2,3-dichlorophenyl H 73 CH₃ morpholin-4-yl —CH₂—CH₂— (S)2,3-dichlorophenyl H 74 CH₃ morpholin-4-yl —CH—CH—CH— 2,3-dichlorophenylH 75 H dimethylamino —CH₂—CH₂—O— (S) 2,3-dimethylphenyl H 76 H3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 77 H3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S) 3,5-dichlorophenyl H 78 Hdimethylamino —CH₂—O— 2,3-dichlorophenyl H 79 H morpholin-4-yl —CH₂—O—2,3-dichlorophenyl H 80 H morpholin-4-yl —CH₂—O— 3-chlorophenyl H 81 Hmorpholin-4-yl —CH₂—O— 3,5-dichlorophenyl H 82 H methoxyethylamino—CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 83 H azetidin-1-yl —CH₂—CH₂—O—(S) 3,5-difluorophenyl H 84 H azetidin-1-yl —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 85 H azetidin-1-yl —CH₂—CH₂—O— (S)2,3-difluorophenyl H 86 H cyclopropylamino —CH₂—CH₂—O— (S)3,5-difluorophenyl H 87 H cyclopropylamino —CH₂—CH₂—O— (S)2,3-difluorophenyl H 88 H cyclopropylamino —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 89 H cyclopropylamino —CH₂—CH₂—O— (S) 3- Htrifluoromethylphenyl 90 H azetidin-1-yl —CH₂—CH₂—O— (S) 3- Htrifluoromethylphenyl 91 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3-difluorophenyl H 92 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)3,5-difluorophenyl H 93 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3- Htrifluoromethylphenyl 94 H hydroxyethylamino —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 95 H 2-hydroxyethylmethylamino —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 96 H dimethylamino —CH₂—O— 3,5-dichlorophenyl H97 H dimethylamino —CH₂—CH₂—O— (S) 3- H trifluoromethoxyphenyl 98 Hdimethylamino —CH₂—CH₂—O— (S) 3-dimethylaminophenyl H 99 H3-fluoroazetidin-1-yl —CH₂—CH₂— (S) 2,3-dichlorophenyl H 100 Hmorpholin-4-yl —CH₂—O— (S) 3,5-dichlorophenyl H 101 H3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 102 CH₃dimethylamino —CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 103 CH₃dimethylamino —CH₂—CH₂—O— (S) 3,5-difluorophenyl H 104 CH₃ dimethylamino—CH₂—CH₂—O— (S) 3- H trifluoromethylphenyl 105 CH₃ dimethylamino—CH₂—CH₂—O— (S) 3- H trifluoromethoxyphenyl 106 CH₃ morpholin-4-yl—CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 107 CH₃ morpholin-4-yl—CH₂—CH₂—O— (S) 3,5-difluorophenyl H 108 CH₃ morpholin-4-yl —CH₂—CH₂—O—(S) 3- H trifluoromethylphenyl 109 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S) 3-H trifluoromethoxyphenyl 110 CH₃ morpholin-4-yl —CH₂—CH₂— (S)2,3,5-trifluorophenyl H 111 CH₃ morpholin-4-yl —CH₂—CH₂— (S)3,5-difluorophenyl H 112 CH₃ morpholin-4-yl —CH₂—CH₂— (S) 3- Htrifluoromethylphenyl 113 CH₃ morpholin-4-yl —CH₂—CH₂— (S) 3- Htrifluoromethoxyphenyl 114 CH₃ dimethylamino —CH₂—CH₂— (S)2,3,5-trifluorophenyl H 115 CH₃ dimethylamino —CH₂—CH₂— (S)3,5-difluorophenyl H 116 CH₃ dimethylamino —CH₂—CH₂— (S) 3- Htrifluoromethylphenyl 117 CH₃ dimethylamino —CH₂—CH₂— (S) 3- Htrifluoromethoxyphenyl 118 H 3-fluoroazetidin-1-yl —CH₂—CH₂— (S)3,5-dichlorophenyl H 119 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 120 H 3-fluoroazetidin-1-yl —CH₂—CH₂— (S)2,3,5-trifluorophenyl H 121 H morpholin-4-yl —CH₂—CH₂— (S) 3- Htrifluoromethoxyphenyl 122 H morpholin-4-yl —CH₂—O— (S)2,3-dichlorophenyl H 123 H 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3-difluorophenyl H 124 H 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3-H trifluoromethylphenyl 125 H 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S)3,5-difluorophenyl H 126 H 3,3-difluoroazetidin-1-yl —CH₂—CH₂— (S)3,5-difluorophenyl H 127 H 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3-H trifluoromethoxyphenyl 128 H morpholin-4-yl —CH₂—CH₂— (S)3,5-difluorophenyl H 129 H morpholin-4-yl —CH₂—CH₂—O— (S)3,4,5-trifluorophenyl H 130 H 3-fluoroazetidin-1-yl —CH₂—CH₂— (S)3,5-difluorophenyl H 131 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3- Htrifluoromethoxyphenyl 132 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2,3-difluorophenyl H 133 CH₃ dimethylamino —CH₂—CH₂—O— (S)2,3-difluorophenyl H 134 CH₃ morpholin-4-yl —CH₂—CH₂— (S)2,3-difluorophenyl H 135 CH₃ dimethylamino —CH₂—CH₂— (S)2,3-difluorophenyl H 136 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3-difluorophenyl H 137 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)3,5-difluorophenyl H 138 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂— (S)2,3-difluorophenyl H 139 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂— (S)3,5-difluorophenyl H 140 H methoxy —CH₂—CH₂—CH₂— (S) 2,3-dichlorophenylH 141 H methoxy —CH₂—CH₂—CH₂— (S) 3,5-dichlorophenyl H 142 H ethoxy—CH₂—CH₂—CH₂— (S) 2,3-dichlorophenyl H 143 H ethoxy —CH₂—CH₂—CH₂— (S)3,5-dichlorophenyl H 144 H methoxy —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H145 H methoxy —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 146 H ethoxy—CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 147 H ethoxy —CH₂—CH₂—O— (S)3,5-dichlorophenyl H 148 H 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3-dichlorophenyl H 149 H methoxy —CH₂—CH₂— (S) 2,3-dichlorophenyl H150 H methoxy —CH₂—CH₂— (S) 3,5-dichlorophenyl H 151 H ethoxy —CH₂—CH₂—(S) 2,3-dichlorophenyl H 152 H ethoxy —CH₂—CH₂— (S) 3,5-dichlorophenyl H153 H 3,3-difluoroazetidin-1-yl —CH₂—O— 2,3-dichlorophenyl H 154 H3,3-difluoroazetidin-1-yl —CH₂—O— 3,5-dichlorophenyl H 155 H3-fluoroazetidin-1-yl —CH₂—O— 2,3-dichlorophenyl H 156 H3-fluoroazetidin-1-yl —CH₂—O— 3,5-dichlorophenyl H 157 CH₃tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 158 CH₃tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 159 CH₃tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2,3,5-trifluorophenyl H 160 CH₃tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2-fluoro-3-chlorophenyl H 161CH₃ tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2-fluoro-5- Htrifluoromethylphenyl 162 CH₃ tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S)naphth-1-yl H 163 CH₃ ethyl —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 164 CH₃ethyl —CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 165 CH ethyl —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 166 CH₃ ethyl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 167 CH₃ ethyl —CH₂—CH₂—O— (S) 2-fluoro-5- Htrifluoromethylphenyl 168 CH₃ ethyl —CH₂—CH₂—O— (S) naphth-1-yl H 169CH₃ isopropyl —CH₂—CH₂—O— (S) 2,3-dichlorophenyl H 170 CH₃ isopropyl—CH₂—CH₂—O— (S) 3,5-dichlorophenyl H 171 CH₃ isopropyl —CH₂—CH₂—O— (S)2,3,5-trifluorophenyl H 172 CH isopropyl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 173 CH₃ isopropyl —CH₂—CH₂—O— (S) 2-fluoro-5-H trifluoromethylphenyl 174 CH₃ isopropyl —CH₂—CH₂—O— (S) naphth-1-yl H175 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S) 2-fluoro-3-chlorophenyl H 176 CH₃morpholin-4-yl —CH₂—CH₂—O— (S) 2-fluoro-5- H trifluoromethylphenyl 177CH₃ morpholin-4-yl —CH₂—CH₂—O— (S) naphth-1-yl H 178 CH dimethylamino—CH₂—CH₂—O— (S) 2-fluoro-3-chlorophenyl H 179 CH₃ dimethylamino—CH₂—CH₂—O— (S) 2-fluoro-5- H trifluoromethylphenyl 180 CH₃dimethylamino —CH₂—CH₂—O— (S) naphth-1-yl H 181 CH₃3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2-fluoro-3-chlorophenyl H 182CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2-fluoro-5- Htrifluoromethylphenyl 183 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S)naphth-1-yl H 184 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 185 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-5- H trifluoromethylphenyl 186 CH₃ 3-fluoroazetidin-1-yl—CH₂—CH₂—O— (S) naphth-1-yl H 187 CH₃ piperidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 188 CH₃ piperidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-5- H trifluoromethylphenyl 189 CH₃ piperidin-1-yl —CH₂—CH₂—O—(S) naphth-1-yl H 190 CH₃ piperidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 191 CH₃ piperidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-5- H trifluoromethylphenyl 192 CH₃ piperidin-1-yl —CH₂—CH₂—O—(S) naphth-1-yl H 193 CH₃ 4,4-difluoropiperidin-1yl —CH₂—CH₂—O— (S)2-fluoro-3-chlorophenyl H 194 CH₃ 4,4-difluoropiperidin-1yl —CH₂—CH₂—O—(S) 2-fluoro-5- H trifluoromethylphenyl 195 CH₃4,4-difluoropiperidin-1yl —CH₂—CH₂—O— (S) naphth-1-yl H 196 CH₃4,4-difluoropiperidin-1yl —CH₂—CH₂—O— (S) 2-fluoro-3-chlorophenyl H 197CH₃ 4,4-difluoropiperidin-1yl —CH₂—CH₂—O— (S) 2-fluoro-5- Htrifluoromethylphenyl 198 CH₃ 4,4-difluoropiperidin-1yl —CH₂—CH₂—O— (S)naphth-1-yl H 199 CH₃ dimethylamino —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H200 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H 201 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H 202 CH₃3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H 203 CH₃tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H 204 CH₃ethyl —CH₂—CH₂—O— (S) 2,5-dichlorophenyl H 205 CH₃ isopropyl —CH₂—CH₂—O—(S) 2,5-dichlorophenyl H 206 CH₃ dimethylamino —CH₂—CH₂—O— (S)2-fluoro-5-chlorophenyl H 207 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2-fluoro-5-chlorophenyl H 208 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2-fluoro-5-chlorophenyl H 209 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O—(S) 2-fluoro-5-chlorophenyl H 210 CH₃ tetrahydro-2H-pyran-4-yl—CH₂—CH₂—O— (S) 2-fluoro-5-chlorophenyl H 211 CH₃ ethyl —CH₂—CH₂—O— (S)2-fluoro-5-chlorophenyl H 212 CH₃ isopropyl —CH₂—CH₂—O— (S)2-fluoro-5-chlorophenyl H 213 CH dimethylamino —CH₂—CH₂—O— (S)2-chloro-5- H trifluoromethylphenyl 214 CH₃ morpholin-4-yl —CH₂—CH₂—O—(S) 2-chloro-5- H trifluoromethylphenyl 215 CH₃ 3-fluoroazetidin-1-yl—CH₂—CH₂—O— (S) 2-chloro-5- H trifluoromethylphenyl 216 CH₃3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2-chloro-5- Htrifluoromethylphenyl 217 CH₃ tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S)2-chloro-5- H trifluoromethylphenyl 218 CH₃ ethyl —CH₂—CH₂—O— (S)2-chloro-5- H trifluoromethylphenyl 219 CH₃ isopropyl —CH₂—CH₂—O— (S)2-chloro-5- H trifluoromethylphenyl 220 CH₃ dimethylamino —CH₂—CH₂—O—(S) 3-fluoro-5- H trifluoromethylphenyl 221 CH₃ morpholin-4-yl—CH₂—CH₂—O— (S) 3-fluoro-5- H trifluoromethylphenyl 222 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 3-fluoro-5- Htrifluoromethylphenyl 223 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S)3-fluoro-5- H trifluoromethylphenyl 224 CH₃ tetrahydro-2H-pyran-4-yl—CH₂—CH₂—O— (S) 3-fluoro-5- H trifluoromethylphenyl 225 CH₃ ethyl—CH₂—CH₂—O— (S) 3-fluoro-5- H trifluoromethylphenyl 224 CH₃ isopropyl—CH₂—CH₂—O— (S) 3-fluoro-5- H trifluoromethylphenyl 225 CH₃dimethylamino —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 226 CH₃morpholin-4-yl —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 227 CH₃3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 228 CH₃3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 229CH₃ tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 230CH₃ ethyl —CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 231 CH₃ isopropyl—CH₂—CH₂—O— (S) 2,3,5-trichlorophenyl H 232 CH₃ dimethylamino—CH₂—CH₂—O— (S) naphth-1-yl H 233 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)naphth-1-yl H 234 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S) naphth-1-ylH 235 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O— (S) naphth-1-yl H 236CH₃ tetrahydro-2H-pyran-4-yl —CH₂—CH₂—O— (S) naphth-1-yl H 237 CH₃ ethyl—CH₂—CH₂—O— (S) naphth-1-yl H 238 CH₃ isopropyl —CH₂—CH₂—O— (S)naphth-1-yl H 239 CH₃ dimethylamino —CH₂—CH₂—O— (S)2,3-dichloro-4-pyridyl H 240 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2,3-dichloro-4-pyridyl H 241 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2,3-dichloro-4-pyridyl H 242 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O—(S) 2,3-dichloro-4-pyridyl H 243 CH₃ tetrahydro-2H-pyran-4-yl—CH₂—CH₂—O— (S) 2,3-dichloro-4-pyridyl H 244 CH₃ ethyl —CH₂—CH₂—O— (S)2,3-dichloro-4-pyridyl H 245 CH₃ isopropyl —CH₂—CH₂—O— (S)2,3-dichloro-4-pyridyl H 246 CH₃ dimethylamino —CH₂—CH₂—O— (S)2-methyl-3-chlorophenyl H 247 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2-methyl-3-chlorophenyl H 248 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2-methyl-3-chlorophenyl H 249 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O—(S) 2-methyl-3-chlorophenyl H 250 CH₃ tetrahydro-2H-pyran-4-yl—CH₂—CH₂—O— (S) 2-methyl-3-chlorophenyl H 251 CH₃ ethyl —CH₂—CH₂—O— (S)2-methyl-3-chlorophenyl H 252 CH₃ isopropyl —CH₂—CH₂—O— (S)2-methyl-3-chlorophenyl H 253 CH₃ dimethylamino —CH₂—CH₂—O— (S)2-methyl-5-chlorophenyl H 254 CH₃ morpholin-4-yl —CH₂—CH₂—O— (S)2-methyl-5-chlorophenyl H 255 CH₃ 3-fluoroazetidin-1-yl —CH₂—CH₂—O— (S)2-methyl-5-chlorophenyl H 256 CH₃ 3,3-difluoroazetidin-1-yl —CH₂—CH₂—O—(S) 2-methyl-5-chlorophenyl H 257 CH₃ tetrahydro-2H-pyran-4-yl—CH₂—CH₂—O— (S) 2-methyl-5-chlorophenyl H 258 CH₃ ethyl —CH₂—CH₂—O— (S)2-methyl-5-chlorophenyl H 259 CH₃ isopropyl —CH₂—CH₂—O— (S)2-methyl-5-chlorophenyl H 260 H methoxy =CH—CH =—CH— 2,3-dichlorophenylH 261 H methoxy =CH—CH =—CH— 3,5-dichlorophenyl H 262 H ethoxy =CH—CH=—CH— 2,3-dichlorophenyl H 263 H ethoxy =CH—CH =—CH— 3,5-dichlorophenylH 264 H dimethylamino =CH—CH =—CH— 3,5-dichlorophenyl H 265 H morpholino=CH—CH =—CH— 3,5-dichlorophenyl H 266 CH₃ dimethylamino =CH—CH =—CH—3,5-dichlorophenyl H 267 CH₃ morpholino =CH—CH =—CH— 2,3-dichlorophenylH 268 CH₃ morpholino =CH—CH =—CH— 3,5-dichlorophenyl H 269 CH₃3,3-difluoroazetidin-1-yl =CH—CH =—CH— 2,3-dichlorophenyl H 270 CH₃3,3-difluoroazetidin-1-yl =CH—CH =—CH— 3,5-dichlorophenyl H 271 CH₃3-fluoroazetidin-1-yl =CH—CH =—CH— 2,3-dichlorophenyl H 272 CH₃3-fluoroazetidin-1-yl =CH—CH =—CH— 3,5-dichlorophenyl H 273 Hdimethylamino =CH—CH =—N— 2,3-dichlorophenyl H 274 H dimethylamino=CH—CH =—N— 3,5-dichlorophenyl H 275 H morpholino =CH—CH =—N—2,3-dichlorophenyl H 276 H morpholino =CH—CH =—N— 3,5-dichlorophenyl H277 H dimethylamino =CH—S— 2,3-dichlorophenyl H 278 H dimethylamino=CH—S— 3,5-dichlorophenyl H 279 H morpholino =CH—S— 2,3-dichlorophenyl H280 H morpholino =CH—S— 3,5-dichlorophenyl H

Table B: Analytical Data

Table B shows the calculated molecular weight (MW) (gram/mol), theobserved MS signal (m/z), the HPLC retention time (Rt) in minutes, andthe HPLC-method as described in above (“Analytics: HPLC-Methods”) usedfor analysis.

TABLE B HPLC HPLC mass No Method Rt signal MW 1 1 1.337 540.1 540.5 2 11.343 512.0 512.5 3 1 1.350 524.0 524.5 4 1 1.262 540.1 540.5 5 1 1.274512.1 512.5 6 1 1.280 524.0 524.5 7 1 1.180 498.0 498.4 8 1 1.183 470.0470.4 9 1 1.232 482.0 482.4 10 1 0.944 498.0 498.4 11 1 0.935 470.0470.4 12 1 0.964 482.0 482.4 13 1 1.193 538.0 538.5 14 1 1.183 534.0534.5 15 1 1.150 526.1 525.5 16 1 1.179 510.1 509.5 17 1 0.831 553.1553.5 18 1 0.960 551.1 551.5 19 1 0.923 553.1 553.5 20 2 1.175 553.0553.5 21 2 1.270 496.1 496.5 22 2 0.981 492.0 492.4 23 1 1.080 484.1483.5 24 1 1.125 508.1 507.6 25 2 1.214 468.1 467.5 26 1 1.139 546.0546.4 27 1 1.135 546.0 546.4 28 2 1.204 498.0 498.4 29 2 1.333 537.1537.5 30 2 1.388 551.1 551.5 31 2 1.386 496.0 496.5 32 2 1.374 538.0538.5 33 1 1.029 496.0 496.5 34 1 0.951 496.1 496.5 35 1 0.973 510.0510.5 36 1 0.919 512.1 512.5 37 1 1.005 506.0 506.4 38 1 1.083 510.1510.5 39 1 1.132 530.0 530.4 40 1 1.136 532.0 531.5 41 2 1.230 516.0515.5 42 1 1.226 540.1 539.6 43 1 1.061 502.1 501.6 44 1 1.043 500.1499.6 45 2 1.198 508.1 507.6 46 1 0.903 466.1 465.5 47 2 1.244 498.1497.5 48 1 0.866 460.1 459.6 49 1 1.344 534.0 534.5 50 1 1.296 492.0492.4 51 1 1.012 466.0 465.5 52 1 1.167 552.0 552.5 53 1 1.109 512.0512.5 54 1 1.213 506.0 506.4 55 1 1.185 558.0 558.5 56 1 1.137 560.0560.4 57 1 1.151 544.0 544.4 58 1 1.311 558.0 558.5 59 1 1.255 560.0560.4 60 1 1.211 544.0 544.4 61 1 1.014 540.0 540.5 62 1 1.010 542.0542.5 63 1 0.997 526.0 526.5 64 1 1.079 540.0 540.5 65 3 0.977 542.0542.5 66 3 0.983 526.0 526.5 67 1 1.363 552.0 552.5 68 1 1.294 554.0554.5 69 1 1.308 538.0 538.5 70 1 1.341 548.0 548.5 71 1 1.239 552.0552.5 72 1 1.172 554.0 554.5 73 1 1.186 538.0 538.5 74 1 1.226 548.0548.5 75 2 1.207 458.2 457.6 76 1 1.299 546.0 546.4 77 1 1.329 530.0530.4 78 1 0.961 484.0 484.4 79 1 1.143 526.0 526.4 80 1 1.190 492.0492.0 81 2 1.288 526.0 526.4 82 1 1.075 514.0 513.5 83 1 0.883 478.1477.5 84 1 0.876 496.1 495.5 85 1 0.905 478.0 477.5 86 1 1.182 478.0477.5 87 1 1.060 478.1 477.5 88 1 1.147 496.0 495.5 89 1 1.196 510.1509.5 90 1 0.920 510.1 509.5 91 1 0.883 496.0 495.5 92 1 1.033 496.0495.5 93 1 1.010 528.1 527.5 94 1 0.879 500.0 499.5 95 1 1.084 514.0513.5 96 1 1.173 484.0 484.4 97 1 1.102 514.1 513.5 98 2 1.197 473.2472.6 99 1 0.956 512.0 512.4 100 1 1.285 526.0 526.4 101 1 1.102 528.0528.4 102 1 0.960 498.1 497.5 103 1 0.904 480.1 479.5 104 1 0.965 512.1511.6 105 1 0.965 528.1 527.6 106 1 1.121 540.1 539.6 107 1 1.106 522.1521.6 108 1 1.202 554.1 553.6 109 1 1.187 570.1 569.6 110 1 1.139 524.1523.6 111 1 1.124 506.0 505.6 112 1 1.179 538.1 537.6 113 1 1.201 554.1553.6 114 1 1.030 482.1 481.5 115 1 1.010 464.1 463.5 116 1 1.068 496.1495.6 117 1 1.080 512.1 511.6 118 1 1.195 512.0 512.4 119 1 1.038 514.0513.5 120 1 1.031 498.0 497.5 121 1 1.285 540.0 539.6 122 1 1.144 526.0526.4 123 1 1.091 514.0 513.5 124 1 1.225 546.0 545.5 125 1 1.192 514.0513.5 126 1 1.217 498.0 497.5 127 1 1.239 562.0 561.5 128 1 1.226 492.0491.6 129 1 1.232 526.0 525.5 130 1 0.991 480.1 479.5 131 1 1.018 544.1543.5 132 1 1.136 522.0 521.6 133 1 0.961 480.0 479.5 134 1 1.124 506.0505.6 135 1 1.000 464.1 463.5 136 1 0.926 510.0 509.5 137 1 0.945 510.0509.5 138 1 0.958 494.0 493.5 139 1 0.978 494.0 493.5

Biological Examples

In Vitro Assay: Ascaridia galli and Oesophagostumum dentatum

Ascaridia galli (intestinal roundworm of chicken), larval stage 3(“L3”); and Oesophagostumum dentatum (nodular worm of swine), larvalstages 3 and 4 (respectively “L3” and “L4”) where suspended in anutrient medium and distributed to 96 well plates with 20 larvae perwell. The wells were spiked DMSO solutions of the compounds withdeclining concentration. The anthelmintic effects were determined bymicroscopic examination and defined by the minimum effectiveconcentration (“MEC”), which is the concentration by which at least oneof the larvae shows mortality, a change in motility or a change inprogression of development.

The following compounds showed an MEC of 50 μM or less against Ascaridiagalli L3: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 21, 23, 24,25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 51, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,68, 69, 71, 72, 73, 75, 78, 79, 81, 83, 85, 86, 87, 88, 89, 91, 94, 95,97, 98, 99

The following compounds showed an MEC of 10 μM or less against Ascaridiagalli L3: 1, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 16, 21, 23, 24, 26, 27,28, 32, 33, 34, 36, 39, 40, 41, 43, 44, 45, 46, 51, 53, 55, 56, 57, 58,59, 62, 63, 65, 66, 68, 71, 72, 73, 75, 79, 85, 91, 99

The following compounds showed an MEC of 50 μM or less againstOesophagostumum dentatum L3: 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14,15, 16, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 51, 53, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 88, 91, 92, 93, 94, 95, 96, 97, 98, 99, 101.

The following compounds showed an MEC of 10 μM or less againstOesophagostumum dentatum L3: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 15,16, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 51, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 79, 81, 83, 84, 85, 91,92, 95, 96, 97, 99.

The following compounds showed an MEC of 50 μM or less againstOesophagostumum dentatum L4: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,15, 16, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 53, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 75, 76, 77, 78, 79, 82, 83,84, 85, 91, 92, 95, 97, 98, 99, 100

The following compounds showed an MEC of 10 μM or less againstOesophagostumum dentatum L4: 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 15,16, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 51, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 71, 72, 73, 75, 78, 79, 83, 84, 85, 91, 92, 95,97, 98, 99.

In Vitro Assay: Haemonchus contortus

Solutions of compounds with declining concentrations in DMSO wereprepared, diluted with nutrient medium and distributed to 96 wellmicrotiter plates. Exsheathed L3 larvae of Haemonchus contortus wereincubated for 20 min at 37° C. in a water bath, separated bycentrifugation and added to the wells with 300 Larvae/well. Afterincubation for 7 days motility was assessed by automated microscopy.Ivermectin was used as positive control, DMSO as negative control andED₅₀ values were calculated which represent the concentration for anindividual compound that reduces motility by 50% with respect to thepositive control.

The following compounds showed an ED₅₀ value below 50 μM againstHaemonchus contortus: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16,21, 23, 25, 26, 27, 28, 32, 33, 34, 35, 36, 38, 39, 41, 42, 43, 44, 45,46, 48, 51, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69,71, 72, 73, 75, 76, 78, 79, 81, 83, 84, 85, 91, 92, 93, 97, 99, 102,103, 104, 105, 106, 107, 108, 110, 111, 113, 114.

The following compounds showed an ED₅₀ value below 10 μM againstHaemonchus contortus: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16,21, 23, 25, 26, 27, 28, 32, 33, 34, 35, 36, 38, 39, 41, 42, 43, 44, 45,46, 48, 51, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69,71, 72, 73, 75, 76, 78, 79, 81, 83, 84, 85, 91, 92, 93, 97, 99, 102,103, 104, 105, 106, 107, 108, 110, 111, 113, 114.

In Vitro Assay: Dirofilaria immitis L1

Approximately 500 D. immitis microfilaria were added to a microtiterplate containing a nutrient medium and the test compound in DMSO atvarying concentrations. After incubation for 3 days, activity wasevaluated as reduction in motility as compared to DMSO as negativecontrol. Compounds were tested in duplicates. Based on the concentrationresponse curves EC₅₀ values were calculated.

The following compounds showed an EC₅₀ value below 10 μM: 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 21, 23, 24, 25, 26, 27, 28,31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 51, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 91, 92, 94, 95,97, 98, 99, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117.

The following compounds showed an EC₅₀ value below 1 μM: 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 21, 23, 24, 25, 26, 27, 28, 31, 32,33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 51, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 91, 92, 94, 95, 97, 98, 99,102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115,116, 117.

The following compounds showed an EC₅₀ value below 0.1 μM: 1, 3, 4, 5,6, 7, 9, 10, 11, 12, 13, 15, 16, 21, 23, 24, 25, 26, 27, 28, 32, 33, 34,35, 36, 38, 39, 40, 41, 42, 44, 45, 46, 51, 53, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 75, 76, 78, 79, 84, 85,91, 92, 95, 97, 99, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117.

In Vitro Assay: Dirofilaria immitis L4

10 larvae L4 of D. immitis were added to a microtiter plate containing anutrient medium and the test compound in DMSO at varying concentrations.After incubation for 3 days, activity was evaluated as reduction inmotility as compared to DMSO as negative control. Compounds were testedin duplicates. Based on the concentration response curves EC₅₀ valueswere calculated.

The following compounds showed an EC₅₀ value below 10 μM: 1, 4, 10, 12.

The following compounds showed an EC₅₀ value below 1 μM: 1, 4, 10, 12.

The following compounds showed an EC₅₀ value below 0.1 μM: 1, 4, 10, 12.

In Vitro Assay: Acanthocheilonema Viteae L1

Approximately 500 A. viteae microfilaria were added to a microtiterplate containing a nutrient medium and the test compound in DMSO atvarying concentrations. After incubation for 3 days, activity wasevaluated as reduction in motility as compared to DMSO as negativecontrol. Compounds were tested in duplicates. Based on the concentrationresponse curves EC₅₀ values were calculated.

The following compounds showed an EC₅₀ value below 10 μM: 1, 3, 7, 10,13, 15, 16, 17, 23, 24, 25, 26, 36, 42, 45, 46, 53, 56, 62, 72.

The following compounds showed an EC₅₀ value below 1 μM: 1, 3, 7, 10,13, 15, 16, 23, 24, 25, 26, 36, 42, 45, 46, 53, 56, 62, 72.

The following compounds showed an EC₅₀ value below 0.1 μM: 1, 3, 7, 10,13, 15, 16, 23, 24, 25, 26, 36, 46, 53, 56, 62, 72.

In Vitro Assay: Agonistic Activity at C. elegans Slo-1a

A CHO K1 cell line stably transfected with the Caenorhabditis elegansslo-1a (accession no Y51A2D.19a) was established. Cells were seeded inmicrotiter plates (black 384-well MTP, clear bottom) in a concentrationof 10,000 cells/well in 25 μl medium and cultured for 20 to 24 hours at37° C. and 5% CO₂. After incubation, 25 l of FMP-dye Blue-Tyrode's wasadded to each well and incubated at room temperature for 30 min. Tenminutes after addition of 12.5 μl compound solution, the plates aretransferred to the FLIPR for measurement.

For the membrane potential measurements, the plates were placed in theFLIPR Penta (Molecular Devices). The baseline measurement of thefluorescence was stared for 20 sec (Exc. 510-545 nm, Emm. 565-625 nm).Potential channel opening measurement was started by addition of 25 μlof KCl-Tyrode (final assay concentration of the KCl-Tyrode: 70 mM KCl, 2mM CaCl₂, 1 mM MgCl₂, 0.8 mM NaH₂PO₄, 5 mM Glucose, 28 mM Hepes, pH 7.4,including the voltage sensitive dye). The complete measurement takes 150s.

EC₅₀ values were determined in triplicate utilizing compound dilutionseries. The data were determined at least in two independent tests. Thedata were proceeded by using the ActivityBase XE Runner software (IDBS)for curve fitting and calculation of the half-maximal effectiveconcentration.

The following compounds showed an EC₅₀ value below 10 μM: 1, 2, 3, 4, 7,8, 9, 10, 11, 12, 15, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35,36, 38, 39, 41, 42, 46, 47, 48, 51, 53, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 74, 75, 78, 85, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 102, 103, 104, 105, 106, 107, 108, 109, 110,111, 112, 113.

The following compounds showed an EC₅₀ value below 1 μM: 1, 3, 4, 7, 9,10, 11, 12, 21, 23, 24, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 38, 39,42, 46, 48, 53, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,71, 72, 73, 75, 85, 91, 95, 97, 98, 99, 102, 103, 104, 105, 106, 107,108, 110, 111, 112, 113.

In Vitro Assay: Agonistic Activity at the Human Maxi K Channel (BKChannel)

A CHO K1 cell line was stably transfected with the KCNMA1 (KCa1.1,U11058) and betal (KCNMB1) subunits of the human Maxi K channel (Ponteet al, Molecular Pharmacology 2012, 81(4), 567-577).

Cells were seeded in microtiter plates (black 384-well MTP, clearbottom) in a concentration of 20,000 cells/well in 25 μl medium andcultured for 20 to 24 hours at 37° C. and 5% CO₂. After incubation, 25 lof FMP-dye Blue-Tyrode's was added to each well and incubated at roomtemperature for 30 min. Ten minutes after addition of 12.5 μl compoundsolution, the plates are transferred to the FLIPR for measurement.

For the membrane potential measurements, plates were placed in the FLIPRPenta (Molecular Devices). The baseline measurement of the fluorescencewas stared for 20 sec (Exc. 510-545 nm, Emm. 565-625 nm). Potentialchannel opening measurement was started by addition of 25 μl KCl-Tyrode(final assay concentration of the KCl-Tyrode: 70 mM KCl, 2 mM CaCl₂, 1mM MgCl₂, 0.8 mM NaH₂PO₄, 5 mM Glucose, 28 mM Hepes, pH 7.4, includingthe voltage sensitive dye). The complete measurement takes 150 s.

EC₅₀ values were determined in triplicate utilizing compound dilutionseries. The data were determined at least in two independent tests. Thedata were proceeded by using the ActivityBase XE Runner software (IDBS)for curve fitting and calculation of the half-maximal effectiveconcentration.

The following compounds showed an EC₅₀ value between 5 and 10 μM: 4, 6,13

The following compounds showed an EC₅₀ value above 30 μM: 1, 2, 3, 5, 7,8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112,113.

In Vivo Assay: Efficacy Against Haemonchus contortus in Jirds

Compounds according to this invention were tested in vivo usingHaemonchus contortus in jirds (Meriones unguiculatus). The jirds wereorally infected with approximately 1500 third-stage larvae of Haemonchuscontortus. Ten days after infection, the jirds in the treatment groupswere treated once either orally or subcutaneously with compounds at adose of 10 mg per kg bodyweight. For treatment, compounds were dissolvedin a mixture of 10% Transcutol, 10% Cremophor EL and 80% physiologicalsodium chloride solution. Three days after treatment, the jirds werenecropsied, and the larvae burden in the stomach was determined. Theefficacy was defined as the reduction of the mean larvae count in theinfected jirds of the treatment group in comparison to the infectedjirds in an untreated control group (negative control).

The following compounds reduced the Haemonchus contortus count by atleast 80% when administered orally or subcutaneously at 10 mg/kg bw.:10, 36, 53, 56, 62, 65, 68, 72, 102.

Thus, it can be seen from the present results that the present compoundsare effective as far as the treatment of nematodes, especiallyDirofilaria, is concerned, while the potential for target-relatedadverse reactions in the host such as mammal (e.g. a human being) islow.

1. Compound of Formula (I)

wherein R¹ is independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5-to 10-membered heterocyclyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,mercapto, NR²R³, COOH, C(═O)OR⁴, SR⁴, SOR⁴, SO₂R⁴, SO₂NR⁵R⁶ andC(═O)NR⁵R⁶, wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto, is optionallysubstituted with one or more substituent(s) independently selected fromthe group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,nitro, hydroxy, mercapto, NR^(2′)R^(3′), C(═O)OR^(4′), SR^(4′),SOR^(4′), SO₂R^(4′), SO₂NR^(5′)R^(6′) and C(═O)NR^(5′)R^(6′), R² and R³are independently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with C₃₋₁₀-cycloalkyl,C₁₋₆-alkyl substituted with 5- to 10-membered heterocyclyl, C₁₋₆-alkylsubstituted with C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to10-membered heteroaryl, or R² and R³ together with the N atom to whichthey are attached form a saturated or unsaturated heterocyclic ringhaving 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms areselected from N, S and O, wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkyl substituted with C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substitutedwith 5- to 10-membered heterocyclyl, C₁₋₆-alkyl substituted withC₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered heteroarylor the heterocyclic ring formed by R² and R³ together with the N atom towhich they are attached is optionally substituted with one or moresubstituent(s) independently selected from the group consisting ofC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto, NR^(2″)R^(3″),C(═O)OR⁴″, SR^(4″), SOR⁴, SO₂R^(4″), SO₂NR^(5″)R^(6″) andC(═O)NR^(5″)R⁶″, R⁴, R⁵ and R⁶ are independently selected from hydrogenand C₁₋₆-alkyl, R^(2′), R^(3′), R^(4′), R^(5′) and R^(6′) areindependently selected from hydrogen and C₁₋₆-alkyl, R^(2″), R^(3″),R^(4″), R^(5″) and R^(6″) are independently selected from hydrogen andC₁₋₆-alkyl, R⁷ is independently selected from the group consisting ofhydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 4-to 10-membered heterocyclyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,mercapto, NR⁸R⁹, COOH, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰, SO₂NR¹¹R¹² andC(═O)NR¹¹R¹², wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₁₀-cycloalkyl, 4- to 10-membered heterocyclyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto, is optionallysubstituted with one or more substituent(s) independently selected fromthe group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano,nitro, hydroxy, mercapto, oxo, NR⁸R^(9′), C(═O)OR^(10′), SR^(10′),SOR^(10′), SO₂R^(10′), SO₂NR^(11′)R^(12′) and C(═O)NR^(11′)R^(12′), R⁸and R⁹ are independently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁₋₆-alkyl substituted with C₃₋₁₀-cycloalkyl,C₁₋₆-alkyl substituted with 5- to 10-membered heterocyclyl, C₁₋₆-alkylsubstituted with C₆₋₁₀-aryl and C₁₋₆-alkyl substituted with 5- to10-membered heteroaryl, or R⁸ and R⁹ together with the N atom to whichthey are attached form a saturated or unsaturated heterocyclic ringhaving 3 to 12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms areselected from N, S and O, wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl,C₁₋₆-alkyl substituted with C₃₋₁₀-cycloalkyl, C₁₋₆-alkyl substitutedwith 5- to 10-membered heterocyclyl, C₁₋₆-alkyl substituted withC₆₋₁₀-aryl or C₁₋₆-alkyl substituted with 5- to 10-membered heteroarylor the heterocyclic ring formed by R⁸ and R⁹ together with the N atom towhich they are attached is optionally substituted with one or moresubstituent(s) independently selected from the group consisting ofC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto, NR^(8″)R^(9″),C(═O)OR^(1″), SR^(10″), SOR^(10″), SO₂R^(10″), SO₂NR^(11″)R^(12″) andC(═O)NR^(11″)R^(12″), R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen and C₁₋₆-alkyl, R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′)are independently selected from hydrogen and C₁₋₆-alkyl, R^(8″), R^(9″),R^(10″), R^(11″) and R^(12″) are independently selected from hydrogenand C₁₋₆-alkyl, R¹³ is hydrogen or C₁₋₃ alkyl, R¹⁴ is hydrogen, C₁₋₃alkyl, C₁₋₃ alkoxy, NR^(14′)R^(14″), wherein R^(14′) and R^(14″) areindependently C₁₋₃-alkyl or R¹³ and R¹⁴ together with the atoms to whichthey are attached form a 5 or 6-carbon atoms containing saturated ring,wherein the saturated ring is optionally substituted with one or moreC₁₋₃-alkyl or ═O, and/or wherein one or more of the ring-forming carbonatoms are optionally replaced by —NH—, —O—, —S(O)—, —S(O)₂— or —S—, orR¹³ and R¹⁴ together with the atoms to which they are attached form a 5or 6-carbon atoms containing unsaturated ring, wherein the unsaturatedring is optionally substituted with one or more C₁₋₃-alkyl, and/orwherein one or more of the ring-forming carbon atoms are optionallyreplaced by —NH—, —N═, ═N—, —O— or —S—, A1 is N or CR¹⁵, wherein R¹⁵ isindependently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, orNR^(15′)R^(5″), wherein R^(15′) and R^(15″) are independentlyC₁₋₃-alkyl, A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen,halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(16′)R^(16″), wherein R^(16′)and R^(16″) are independently C₁₋₃-alkyl, A3 is N or CR¹⁷, wherein R¹⁷is independently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, orNR^(17′)R^(17″), wherein R^(17′) and R^(17″) are independentlyC₁₋₃-alkyl, A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen,halogen C₁₋₃ alkyl, C₁₋₃ alkoxy, or NR^(18′)R¹⁸″, wherein R^(18′) andR^(18″) are independently C₁₋₃-alkyl, R¹⁹ is independently selected fromthe group consisting of C₆₋₁₀-aryl and 5- to 10-membered heteroaryl,wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl is optionallysubstituted with one or more substituent(s) independently selected fromthe group consisting of C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 5-to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, C₁₋₆-alkylmercapto, halogen, cyano, nitro, hydroxy,mercapto, NR²⁰R²¹, C(═O)OR²², SR²², SOR²², SO₂R²², SO₂NR²³R²⁴ andC(═O)NR²³R²⁴, R²⁰ and R²¹ are independently selected from the groupconsisting of hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy-C₁₋₆-alkyl, C₁-C₆-alkyl substitutedwith C₆₋₁₀-aryl, C₁₋₆-alkyl substituted with 5- to 10-memberedheteroaryl, or R²⁰ and R²¹ together with the N atom to which they areattached form a saturated or unsaturated heterocyclic ring having 3 to12 ring atoms, wherein 0, 1, 2, or 3 further ring atoms are selectedfrom N, S and O, wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to10-membered heteroaryl, C₁₋₆-alkoxy or C₁₋₆-alkylmercapto or theheterocyclic ring formed by R²⁰ and R²¹ together with the N atom towhich they are attached is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₁₀-cycloalkyl, 5- to10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, carbonyl, halogen, cyano, hydroxy, mercapto,NR^(20′)R^(21′), C(═O)OR^(22′), SR^(22′), SOR^(22′), SO₂R^(22′),SO₂NR^(23′)R^(24′) and C(═O)NR^(23′)R^(24′), R²², R²³ and R²⁴ areindependently selected from hydrogen and C₁₋₆-alkyl, R^(20′), R^(21′),R^(22′), R^(23′) and R^(24′) are independently selected from hydrogenand C₁₋₆-alkyl, R²⁵ is independently selected from hydrogen andC₁₋₆-alkyl, or a stereoisomer, physiologically acceptable salt, ester,solvate, polymorph, prodrug and mixtures thereof.
 2. The compoundaccording to claim 1, wherein R¹ is independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano,nitro, hydroxy, NR²R³, C(═O)OR⁴ and C(═O)NR⁵R⁶, wherein each C₁₋₆-alkylor C₁₋₆-alkoxy is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy and NR^(2′)R^(3′), R² and R³are independently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl and 5 to 10-memberedheteroaryl, or R² and R³ together with the N atom to which they areattached form a saturated or unsaturated heterocyclic ring having 3 to12 ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2 or 3 furtherring atoms are selected from N, S and O, wherein each C₁₋₆-alkyl,C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl or 5 to 10-membered heteroaryl or theheterocyclic ring formed by R² and R³ together with the N atom to whichthey are attached is optionally substituted with one or moresubstituent(s) independently selected from the group consisting ofC₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₁₋₆-alkoxy, R⁴, R⁵ and R⁶ areindependently selected from hydrogen and C₁₋₆-alkyl, R^(2′) and R^(3′)are independently selected from hydrogen and C₁₋₆-alkyl.
 3. The compoundaccording to claim 1, wherein R¹ is independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy and halogen,wherein each C₁₋₆-alkyl or C₁₋₆-alkoxy is optionally substituted withone or more substituent(s) independently selected from the groupconsisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy andNR^(2′)R^(3′), wherein R^(2′) and R^(3′) are independently selected fromhydrogen and C₁₋₃-alkyl.
 4. The compound according to claim 1, whereinR¹ is independently selected from the group consisting of hydrogen,methyl, trifluoromethyl, ethyl, methoxy, ethoxy, fluoride and chloride.5. The compound according to claim 1, wherein R⁷ is independentlyselected from the group consisting of hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₁₀-cycloalkyl, 4- to 10 membered heterocyclyl,C₁₋₆-alkoxy, halogen, cyano, hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰,SO₂R¹⁰ and C(═O)NR¹¹R¹² wherein each C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₁₀-cycloalkyl, 4- to 10 membered heterocyclyl or C₁₋₆-alkoxy isoptionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5-to 10 membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,NR^(8′)R^(9′), C(═O)OR^(10′), and C(═O)NR¹¹R¹², R⁸ and R⁹ areindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to 10 membered heterocyclyland 5- to 10 membered heteroaryl, or R⁸ and R⁹ together with the N atomto which they are attached form a saturated or unsaturated heterocyclicring having 3 to 12 ring atoms, wherein 1 ring atom is N and wherein 0,1, 2, or 3 further ring atoms are selected from N, S and O; wherein eachC₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, 5- to 10 memberedheterocyclyl, and 5- to 10 membered heteroaryl or the heterocyclic ringformed by R⁸ and R⁹ together with the N atom to which they are attachedis optionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen,cyano, hydroxy, NR^(8″)R^(9″), C(═O)—OR^(10″) and C(═O)NR^(11″)R^(12″);R¹⁰, R¹¹ and R¹² are independently selected from hydrogen andC₁₋₆-alkyl, R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) areindependently selected from hydrogen and C₁₋₆-alkyl, R^(8″), R^(9″),R^(10″), R^(11″) and R^(12″) are independently selected from hydrogenand C₁₋₆-alkyl.
 6. The compound according to claim 1, wherein R⁷ isindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered heterocyclyl, C₁₋₆-alkoxy,hydroxy, NR⁸R⁹, C(═O)OR¹⁰, SR¹⁰, SOR¹⁰, SO₂R¹⁰ and C(═O)NR¹¹R¹² whereineach C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10 membered heterocyclyl orC₁₋₆-alkoxy is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₁₋₆-alkyl, 5- to 10membered heterocyclyl, C₁₋₆-alkoxy, halogen, cyano, hydroxy, oxo,NR^(8′)R^(9′), C(═O)OR^(10′) and C(═O)NR^(11′)R^(12′), R⁸ and R⁹ areindependently selected from the group consisting of hydrogen,C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₆₋₁₀-aryl, and 5- to 10 memberedheteroaryl, or R⁸ and R⁹ together with the N atom to which they areattached form a saturated or unsaturated heterocyclic ring having 3 to12 ring atoms, wherein 1 ring atom is N and wherein 0, 1, 2, or 3further ring atoms are selected from N, S and O; wherein the C₁₋₆-alkyl,C₆₋₁₀-aryl, and 5- to 10 membered heteroaryl or the heterocyclic ringformed by R⁸ and R⁹ together with the N atom to which they are attachedis optionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxyand NR^(8″)R^(9″), R¹⁰, R¹¹ and R¹² are independently selected fromhydrogen or C₁₋₆-alkyl, R^(8′), R^(9′), R^(10′), R^(11′) and R^(12′) areindependently selected from hydrogen or C₁₋₆-alkyl, R^(8″) are R^(9″)are independently selected from hydrogen or C₁₋₆-alkyl.
 7. The compoundaccording to claim 1, wherein R⁷ is independently selected from thegroup consisting of hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, 4- to 10membered heterocyclyl, C₁₋₆-alkoxy, NR⁸R⁹, wherein each C₁₋₆-alkyl,C₂₋₆-alkenyl, 4- to 10 membered heterocyclyl or C₁₋₆-alkoxy isoptionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, andhalogen, R⁸ and R⁹ are independently selected from the group consistingof hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, wherein the C₁₋₆-alkyl, orC₃₋₆-cycloalkyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting ofC₁₋₆-alkyl, C₁₋₆-alkoxy, and hydroxy.
 8. The compound according to claim1, wherein R¹³ and R¹⁴ together with the atoms to which they areattached form a 5 or 6-carbon atoms containing saturated ring, whereinthe saturated ring is optionally substituted with one or more C₁₋₃-alkylor ═O, and/or wherein one or more of the ring-forming carbon atoms areoptionally replaced by —NH—, —O—, —S(O)—, —S(O)₂— or —S—, or R¹³ and R¹⁴together with the atoms to which they are attached form a 5 or 6-carbonatoms containing unsaturated ring, wherein the unsaturated ring isoptionally substituted with one or more C₁₋₃-alkyl, and/or wherein oneor more of the ring-forming carbon atoms are optionally replaced by—NH—, —N═, ═N—, —O— or —S—, A1 is N or CR¹⁵, wherein R¹⁵ isindependently hydrogen, halogen C₁₋₃ alkyl, C₁₋₃ alkoxy orNR^(15′)R^(15″), wherein R^(15′) and R^(15″) are independentlyC₁₋₃-alkyl, A2 is N or CR¹⁶, wherein R¹⁶ is independently hydrogen,halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) andR^(16″) are independently C₁₋₃-alkyl, A3 is N or CR¹⁷, wherein R¹⁷ isindependently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy orNR^(15′)R^(15″), wherein R^(15′) and R^(15″) are independentlyC₁₋₃-alkyl, A4 is N or CR¹⁸, wherein R^(1″) is independently hydrogen,halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15′)R¹⁵″, wherein R^(15′) andR^(15″) are independently C₁₋₃-alkyl.
 9. The compound according to claim1, wherein R¹³ and R¹⁴ together with the atoms to which they areattached form a 5 or 6-carbon atoms containing saturated ring, whereinone or more of the ring-forming carbon atoms are optionally replaced by—NH—, —O— or —S—, or R¹³ and R¹⁴ together with the atoms to which theyare attached form a 5 or 6-carbon atoms containing unsaturated ring,wherein one or more of the ring-forming carbon atoms are optionallyreplaced by —NH—, —N═, ═N—, —O— or —S—, A1 is CR^(15′) wherein R¹⁵ isindependently hydrogen, halogen C₁₋₃ alkyl, C₁₋₃ alkoxy orNR^(15′)R^(15″), wherein R^(15′) and R^(15″) are independentlyC₁₋₃-alkyl, A2 is CR¹⁶, wherein R¹⁶ is independently hydrogen, halogen,C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), wherein R^(16′) and R^(16″)are independently C₁₋₃-alkyl, A3 is CR¹⁷, wherein R¹⁷ is hydrogen, A4 isCR¹⁸, wherein R¹⁸ is hydrogen.
 10. The compound according to claim 1,wherein R¹³ and R¹⁴ together with the atoms to which they are attachedform a 5 or 6-carbon atoms containing saturated ring, wherein one ormore of the ring-forming carbon atoms are optionally replaced by —NH—,—O— or —S—, A1 is CR¹⁵ wherein R¹⁵ is independently hydrogen, halogenC₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(15′)R^(15″), wherein R^(15′) and R^(15″)are independently C₁₋₃-alkyl, A2 is CR¹⁶, wherein R¹⁶ is independentlyhydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy or NR^(16′)R^(16″), whereinR^(16′) and R^(16″) are independently C₁₋₃-alkyl, A3 is CR¹⁷, whereinR¹⁷ is hydrogen, A4 is CR¹⁸, wherein R¹⁸ is hydrogen.
 11. The compoundaccording to claim 1, wherein none, one or two of residues A1, A2, A3and A4 is N.
 12. The compound according to claim 1, wherein R¹⁹ isindependently selected from the group consisting of R¹⁹ is independentlyselected from the group consisting of C₆₋₁₀-aryl and 5- to 10-memberedheteroaryl, wherein each C₆₋₁₀-aryl or 5- to 10-membered heteroaryl isoptionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5-to 10-membered heterocyclyl, C₆₋₁₀-aryl, 5- to 10-membered heteroaryl,C₁₋₆-alkoxy, halogen, cyano, nitro, hydroxy, NR²⁰R²¹, C(═O)OR²² andC(═O)N²³R²⁴, R²⁰ and R²¹ are independently selected from the groupconsisting of hydrogen, C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl and C₆₋₁₀-aryl orR²⁰ and R²¹ together with the N atom to which they are attached form asaturated or unsaturated heterocyclic ring having 3 to 12 ring atoms,wherein 0, 1, 2, or 3 further ring atoms are selected from N, S and O;wherein each C₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, C₁₋₆-alkoxy, or C₆₋₁₀-aryl orthe heterocyclic ring formed by R²⁰ and R²¹ together with the N atom towhich they are attached is optionally substituted with one or moresubstituents independently selected from the group consisting ofC₁₋₆-alkyl, C₃₋₁₀-cycloalkyl, 5- to 10-membered heterocyclyl,C₆₋₁₀-aryl, 5- to 10-membered heteroaryl, C₁₋₆-alkoxy, halogen, cyano,hydroxy, NR^(20′)R^(21′), C(═O)OR^(22′) and C(═O)NR^(23′)R^(24′) R²²,R²³ and R²⁴ are independently selected from hydrogen and C₁₋₆-alkyl,R^(20′), R^(21′), R^(22′), R^(23′) and R^(24′) are independentlyselected from hydrogen and C₁₋₆-alkyl.
 13. The compound according toclaim 1, wherein R¹⁹ is independently selected from the group consistingof C₆₋₁₀-aryl and 5- to 10-membered heteroaryl wherein each C₆₋₁₀-arylor 5- to 10-membered heteroaryl is optionally substituted with one ormore substituent(s) independently selected from the group consisting ofC₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, cyano, nitro and hydroxy, wherein eachC₁₋₆-alkyl, C₁₋₆-alkoxy, is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, cyano, hydroxy, wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy, isoptionally substituted with one or more halogen.
 14. The compoundaccording to claim 1, wherein R¹⁹ is C₆₋₁₀-aryl, wherein the C₆₋₁₀-arylis optionally substituted with one or more substituent(s) independentlyselected from the group consisting of C₁₋₆-alkyl, halogen, C₁₋₆-alkoxycyano and nitro wherein each C₁₋₆-alkyl, C₁₋₆-alkoxy is optionallysubstituted with one or more halogen.
 15. The compound according toclaim 1, wherein R²⁵ is hydrogen.
 16. Process for preparing the compoundaccording to Formula (I) comprising the step of reacting a compound ofFormula (A)

with a compound of Formula (B)

wherein R¹, R⁷, R¹³, R¹⁴, A1, A2, A3, A4, R¹⁹ and R²⁵ are defined as inclaim 1, to obtain the compound according to Formula (I).
 17. AVeterinary composition comprising compound according to Formula (I)according to claim 1, and one or more physiologically acceptableexcipient(s). 18-20. (canceled)
 21. A method of treating a diseasecaused by helminths which comprises administering to an animal atherapeutically effective amount of a compound according to Formula (I)according to claim
 1. 22. A method of treating a disease according toclaim 21 wherein the disease is the heartworm disease.
 23. A method oftreating a disease caused by helminths which comprises administering toan animal, a therapeutically effective amount of the veterinarycomposition according to claim
 17. 24. A method of treating a diseaseaccording to claim 23 wherein the disease is the heartworm disease.